Pyrazole compounds as modulators of FSHR and uses thereof

ABSTRACT

The present invention relates to pyrazole compounds, and pharmaceutically acceptable compositions thereof, useful as positive allosteric modulators of follicle stimulating hormone receptor (FSHR).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No.15/321,249, now U.S. Pat. No. 10,208,055, filed Dec. 22, 2016, which isa U.S. National Stage Application under 35 U.S.C. § 371 of InternationalApplication No. PCT/CN2014/094459, filed Dec. 22, 2014, which claimspriority to PCT/CN2014/080519, filed Jun. 23, 2014, the entire contentsof each of which are incorporated herein by reference in their entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to pyrazole compounds useful as agonistsof follicle stimulating hormone receptor (FSHR). The invention alsoprovides pharmaceutically acceptable compositions comprising compoundsof the present invention and methods of using said compositions in thetreatment of various disorders.

BACKGROUND OF THE INVENTION

Gonadotropins serve important functions in a variety of bodily functionsincluding metabolism, temperature regulation and the reproductiveprocess. Gonadotropins act on specific gonadal cell types to initiateovarian and testicular differentiation and steroidogenesis. Thegonadotropin FSH (follicle stimulating hormone) is released from theanterior pituitary under the influence of gonadotropin-releasing hormoneand estrogens, and from the placenta during pregnancy. FSH is aheterodimeric glycoprotein hormone that shares structural similaritieswith luteinizing hormone (LH) and thyroid stimulating hormone (TSH),both of which are also produced in the pituitary gland, and chorionicgonadotropin (CG), which is produced in the placenta. In the female, FSHplays a pivotal role in the stimulation of follicle development andmaturation and in addition, it is the major hormone regulating secretionof estrogens, whereas LH induces ovulation. In the male, FSH isresponsible for the integrity of the seminiferous tubules and acts onSertoli cells to support gametogenesis.

The hormones are relatively large (28-38 kDa) and are composed of acommon α-subunit non-covalently bound to a distinct β-subunit thatconfers receptor binding specificity. The cellular receptor for thesehormones is expressed on testicular Sertoli cells and ovarian granulosacells. The FSH receptor is known to be members of the G protein-coupledclass of membrane-bound receptors, which when activated stimulate anincrease in the activity of adenylyl cyclase. This results in anincrease in the level of the intracellular second messenger adenosine3′,5′-monophosphate (cAMP), which in turn causes increased steroidsynthesis and secretion. Hydropathicity plots of the amino acidsequences of these receptors reveal three general domains: a hydrophilicamino-terminal region, considered to be the amino-terminal extracellulardomain; seven hydrophobic segments of membrane-spanning length,considered to be the transmembrane domain; and a carboxy-terminal regionthat contains potential phosphorylation sites (serine, threonine, andtyrosine residues), considered to be the carboxy-terminal intracellularor cytoplasmic domain. The glycoprotein hormone receptor family isdistinguished from other G protein-coupled receptors, such as theβ-2-adrenergic, rhodopsin, and substance K receptors, by the large sizeof the hydrophilic amino-terminal domain, which is involved in hormonebinding.

Annually in the U.S. there are 2.4 million couples experiencinginfertility that are potential candidates for treatment. FSH, eitherextracted from urine or produced by recombinant DNA technology, is aparenterally-administered protein product used by specialists forovulation induction and for controlled ovarial hyperstimulation. Whereasovulation induction is directed at achieving a single follicle toovulate, controlled ovarial hyperstimulation is directed at harvestingmultiple oocytes for use in various in-vitro assisted reproductivetechnologies, e.g. in-vitro fertilization (IVF). FSH is also usedclinically to treat male hypogonadism and male infertility, e.g. sometypes of failure of spermatogenesis.

FSHR is a highly specific target in the ovarian follicle growth processand is exclusively expressed in the ovary. However, the use of FSH islimited by its high cost, lack of oral dosing, and need of extensivemonitoring by specialist physicians. Hence, identification of anon-peptidic small molecule substitute for FSH that could potentially bedeveloped for oral administration is desirable. Low molecular weight FSHmimetics with agonistic properties are disclosed in the internationalapplications WO 2002/09706 and WO 2010/136438 as well as the U.S. Pat.No. 6,653,338. There is still a need for low molecular weight hormonemimetics that selectively activate FSHR.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asmodulators of FSHR. Such compounds have general formula I or formula II:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,X, Y, Z, R¹, R², R³, R⁴, R⁵, R⁶, n, and p, is as defined and describedin embodiments herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with abnormal cellular responsestriggered by follicle stimulating hormone events. Such diseases,disorders, or conditions include those described herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Invention

In certain embodiments, the present invention provides modulators offollicle stimulating hormone receptor (FSHR). In certain embodiments,the present invention provides positive allosteric modulators of FSHR.In some embodiments, such compounds include those of the formulaedescribed herein, or a pharmaceutically acceptable salt thereof, whereineach variable is as defined and described herein.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75 Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Exemplary aliphatic groups are linear or branched, substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl groups andhybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, orphosphorus (including, any oxidized form of nitrogen, sulfur, orphosphorus; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic andbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains three to seven ring members. The term “aryl”is used interchangeably with the term “aryl ring”. In certainembodiments of the present invention, “aryl” refers to an aromatic ringsystem. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyland the like, which optionally includes one or more substituents. Alsoincluded within the scope of the term “aryl”, as it is used herein, is agroup in which an aromatic ring is fused to one or more non-aromaticrings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thiophenyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group is optionally mono- or bicyclic. The term “heteroaryl”is used interchangeably with the terms “heteroaryl ring”, “heteroarylgroup”, or “heteroaromatic”, any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “thienyl” and “thiophenyl” are usedinterchangeably and refer to a 5-membered monocyclic heteroaryl ringcontaining a single sulfur heteroatom.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl),or +NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclicgroup”, “heterocyclic moiety”, and “heterocyclic radical”, are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group is optionally mono- or bicyclic.The term “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, certain compounds of the invention contain“optionally substituted” moieties. In general, the term “substituted”,whether preceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. “Substituted” applies to one or more hydrogens that areeither explicit or implicit from the structure (e.g.,

refers to at least

refers to at least

Unless otherwise indicated, an “optionally substituted” group has asuitable substituent at each substitutable position of the group, andwhen more than one position in any given structure is substituted withmore than one substituent selected from a specified group, thesubstituent is either the same or different at every position.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable”, as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently deuterium; halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which are optionallysubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which is optionallysubstituted with R^(∘); —CH═CHPh, which is optionally substituted withR^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which is optionally substituted withR^(∘); —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘), SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘),—(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straightor branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) is optionally substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which is optionally substituted as definedbelow.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently deuterium, halogen, —(CH₂)₀₋₂R^(•),-(haloR^(•)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂;—O(haloR^(•)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH,—(CH₂)₀₋₂C(O)OR^(•), —(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂,—(CH₂)₀₋₂NHR^(•), —(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃,—C(O)SR^(•), —(C₁₋₄ straight or branched alkylene)C(O)OR^(•), or—SSR^(•) wherein each R^(•) is unsubstituted or where preceded by “halo”is substituted only with one or more halogens, and is independentlyselected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents on a saturated carbon atom of R^(∘) include ═O and═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which is substituted as defined below, oran unsubstituted 5-6-membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which is optionally substitutedas defined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which is optionallysubstituted as defined below, unsubstituted —OPh, or an unsubstituted5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable sulfur of an “optionallysubstituted” group include ═O, (═O)₂, —R^(†), —NR^(†) ₂, -(═O)NR^(†) ₂,-(═O)₂NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†), —C(O)C(O)R^(†),—C(O)CH₂C(O)R^(†), —C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or—N(R^(†))S(O)₂R^(†); wherein each R^(†) is independently hydrogen, C₁₋₆aliphatic which is optionally substituted as defined below, or anunsubstituted 5-6-membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or, notwithstanding the definition above, twoindependent occurrences of R^(†), taken together with their interveningatom(s) form an unsubstituted 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain embodiments, the terms “optionally substituted”, “optionallysubstituted alkyl,” “optionally substituted” optionally substitutedalkenyl,” “optionally substituted alkynyl”, “optionally substitutedcarbocyclic,” “optionally substituted aryl”, “optionally substitutedheteroaryl,” “optionally substituted heterocyclic,” and any otheroptionally substituted group as used herein, refer to groups that aresubstituted or unsubstituted by independent replacement of one, two, orthree or more of the hydrogen atoms thereon with typical substituentsincluding, but not limited to:

—F, —Cl, —Br, —I, deuterium,

—OH, protected hydroxy, alkoxy, oxo, thiooxo,

—NO₂, —CN, CF₃, N₃,

—NH₂, protected amino, —NH alkyl, —NH alkenyl, —NH alkynyl, —NHcycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocyclic, -dialkylamino,-diarylamino, -diheteroarylamino,

—O— alkyl, —O— alkenyl, —O— alkynyl, —O— cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocyclic,

—C(O)— alkyl, —C(O)— alkenyl, —C(O)— alkynyl, —C(O)— carbocyclyl,—C(O)-aryl, —C(O)— heteroaryl, —C(O)-heterocyclyl,

—CONH₂, —CONH— alkyl, —CONH— alkenyl, —CONH— alkynyl, —CONH-carbocyclyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocyclyl,

—OCO₂— alkyl, —OCO₂— alkenyl, —OCO₂— alkynyl, —OCO₂— carbocyclyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocyclyl, —OCONH₂, —OCONH—alkyl, —OCONH— alkenyl, —OCONH— alkynyl, —OCONH— carbocyclyl, —OCONH—aryl, —OCONH— heteroaryl, —OCONH— heterocyclyl,

—NHC(O)— alkyl, —NHC(O)— alkenyl, —NHC(O)— alkynyl, —NHC(O)—carbocyclyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclyl,—NHCO₂— alkyl, —NHCO₂— alkenyl, —NHCO₂— alkynyl, —NHCO₂— carbocyclyl,—NHCO₂— aryl, —NHCO₂— heteroaryl, —NHCO₂— heterocyclyl, —NHC(O)NH₂,—NHC(O)NH— alkyl, —NHC(O)NH— alkenyl, —NHC(O)NH— alkenyl, —NHC(O)NH—carbocyclyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH—heterocyclyl, NHC(S)NH₂, —NHC(S)NH— alkyl, —NHC(S)NH— alkenyl,—NHC(S)NH— alkynyl, —NHC(S)NH— carbocyclyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocyclyl, —NHC(NH)NH₂, —NHC(NH)NH—alkyl, —NHC(NH)NH— alkenyl, —NHC(NH)NH— alkenyl, —NHC(NH)NH—carbocyclyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH—heterocyclyl, —NHC(NH)— alkyl, —NHC(NH)— alkenyl, —NHC(NH)— alkenyl,—NHC(NH)— carbocyclyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocyclyl,

—C(NH)NH— alkyl, —C(NH)NH— alkenyl, —C(NH)NH— alkynyl, —C(NH)NH—carbocyclyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocyclyl,

—S(O)— alkyl, —S(O)— alkenyl, —S(O)— alkynyl, —S(O)— carbocyclyl,—S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocyclyl —SO₂NH₂, —SO₂NH— alkyl,—SO₂NH— alkenyl, —SO₂NH— alkynyl, —SO₂NH— carbocyclyl, —SO₂NH— aryl,—SO₂NH— heteroaryl, —SO₂NH— heterocyclyl,

—NHSO₂— alkyl, —NHSO₂— alkenyl, —NHSO₂— alkynyl, —NHSO₂— carbocyclyl,—NHSO₂-aryl, —NHSO₂-heteroaryl, —NHSO₂-heterocyclyl,

—CH₂NH₂, —CH₂SO₂CH₃,

-mono-, di-, or tri-alkyl silyl,

-alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl,-heteroarylalkyl, heterocycloalkyl, -cycloalkyl, -carbocyclic,-heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy,-methoxyethoxy, —SH, —S— alkyl, —S— alkenyl, —S— alkynyl, —S—carbocyclyl, —S-aryl, —S-heteroaryl, —S-heterocyclyl, ormethylthiomethyl.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. In some embodiments, the groupcomprises one or more deuterium atoms.

There is furthermore intended that a compound of formula (I) or formula(II) includes isotope-labeled forms thereof. An isotope-labeled form ofa compound of formula (I) or formula (II) is identical to this compoundapart from the fact that one or more atoms of the compound have beenreplaced by an atom or atoms having an atomic mass or mass number whichdiffers from the atomic mass or mass number of the atom which usuallyoccurs naturally. Examples of isotopes which are readily commerciallyavailable and which can be incorporated into a compound of formula (I)or formula (II) by well-known methods include isotopes of hydrogen,carbon, nitrogen, oxygen, phos-phorus, fluo-rine and chlorine, forexample ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ^(18F) and ³⁶Cl,respectively. A compound of formula (I) or formula (II), a prodrug,thereof or a pharmaceutically acceptable salt of either which containsone or more of the above-mentioned isotopes and/or other isotopes ofother atoms is intended to be part of the present invention. Anisotope-labeled compound of formula (I) or formula (II) can be used in anumber of beneficial ways. For example, an isotope-labeled compound ofthe formula (I) or formula (II) into which, for example, a radioisotope,such as ³H or ¹⁴C, has been incorporated, is suitable for medicamentand/or substrate tissue distribution assays. These radioisotopes, i.e.tritium (³H) and carbon-14 (¹⁴C), are particularly preferred owing tosimple preparation and excellent detectability. Incorporation of heavierisotopes, for example deuterium (²H), into a compound of formula (I) orformula (II) has therapeutic advantages owing to the higher metabolicstability of this isotope-labeled compound. Higher metabolic stabilitytranslates directly into an increased in vivo half-life or lowerdosages, which under most circumstances would represent a preferredembodiment of the present invention. An isotope-labeled compound offormula (I) or formula (II) can usually be prepared by carrying out theprocedures disclosed in the synthesis schemes and the relateddescription, in the example part and in the preparation part in thepresent text, replacing a non-isotope-labeled reactant by a readilyavailable isotope-labeled reactant.

Deuterium (²H) can also be incorporated into a compound of formula (I)or formula (II) for the purpose in order to manipulate the oxidativemetabolism of the compound by way of the primary kinetic isotope effect.The primary kinetic isotope effect is a change of the rate for achemical reaction that results from exchange of isotopic nuclei, whichin turn is caused by the change in ground state energies necessary forcovalent bond formation after this isotopic exchange. Exchange of aheavier isotope usually results in a lowering of the ground state energyfor a chemical bond and thus causes a reduction in the rate inrate-limiting bond breakage. If the bond breakage occurs in or in thevicinity of a saddle-point region along the coordinate of amulti-product reaction, the product distribution ratios can be alteredsubstantially. For explanation: if deuterium is bonded to a carbon atomat a non-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a com-poundof formula (I) or formula (II) that is susceptible to oxidation, theprofile of this compound in vivo can be drastically modified and resultin improved pharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art is able to optimize pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of formula (I) or formula (II) with improvedstability through resistance to such oxidative metabolism. Significantimprovements in the pharmacokinetic profiles of compounds of formula (I)or formula (II) are thereby obtained, and can be expressedquantitatively in terms of increases in the in vivo half-life (t/2),concentration at maximum therapeutic effect (C_(max)), area under thedose response curve (AUC), and F; and in terms of reduced clearance,dose and materials costs.

The following is intended to illustrate the above: a compound of formula(I) or formula (II) which has multiple potential sites of attack foroxidative metabolism, for example benzylic hydrogen atoms and hydrogenatoms bonded to a nitrogen atom, is prepared as a series of analogues inwhich various combinations of hydrogen atoms are replaced by deuteriumatoms, so that some, most or all of these hydrogen atoms have beenreplaced by deuterium atoms. Half-life determinations enable favorableand accurate determination of the extent of the extent to which theimprovement in resistance to oxidative metabolism has improved. In thisway, it is determined that the half-life of the parent compound can beextended by up to 100% as the result of deuterium-hydrogen exchange ofthis type.

Deuterium-hydrogen exchange in a compound of formula (I) or formula (II)can also be used to achieve a favorable modification of the metabolitespectrum of the starting compound in order to diminish or eliminateundesired toxic metabolites. For example, if a toxic metabolite arisesthrough oxidative carbon-hydrogen (C—H) bond cleavage, it can reasonablybe assumed that the deuterated analogue will greatly diminish oreliminate production of the unwanted metabolite, even if the particularoxidation is not a rate-determining step. Further information on thestate of the art with respect to deuterium-hydrogen exchange may befound, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990,Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res.14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, andJarman et al. Carcinogenesis 16(4), 683-688, 1993.

As used herein, the term “modulator” is defined as a compound that bindsto and/or inhibits the target with measurable affinity. In certainembodiments, a modulator has an IC₅₀ and/or binding constant of lessabout 50 μM, less than about 1 μM, less than about 500 nM, less thanabout 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in FSHR activity between a samplecomprising a compound of the present invention, or composition thereof,and FSHR, and an equivalent sample comprising FSHR, in the absence ofsaid compound, or composition thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

3. Description of Exemplary Compounds

According to one aspect, the present invention provides a compound offormula I,

or a pharmaceutically acceptable salt thereof, wherein:

-   X is O, S, SO, SO₂, or NR;-   Y is O, S, or NR;-   Z is O, S, SO, SO₂, or N; wherein when Z is O, S, SO, or SO₂, then p    is 0;-   each R is independently hydrogen, C₁₋₆ aliphatic, aryl, a 3-8    membered saturated or partially unsaturated carbocyclic ring, a 3-7    membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur; each of which is    optionally substituted; or-   two R groups on the same atom are taken together with the atom to    which they are attached to form an aryl ring, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted;-   Ring A is a fused aryl, a fused 3-8 membered saturated or partially    unsaturated carbocyclic ring, a fused 3-7 membered heterocylic ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or a fused 5-6 membered monocyclic heteroaryl ring having    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur;-   R¹ is —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂,    —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂;-   R² is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR,    —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or    —N(R)₂;-   R³ is an optionally substituted aryl;-   each R⁴ is independently —R, halogen, -haloalkyl, —OR, —SR, —CN,    —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R,    —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂;-   R⁵ is C₁₋₆ aliphatic, —SO₂R, —SOR, aryl, a 3-8 membered saturated or    partially unsaturated carbocyclic ring, a 3-7 membered heterocylic    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur; each of which is optionally substituted;-   R⁶ is hydrogen, C₁₋₆ aliphatic, —SO₂R, —SOR, aryl, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted;-   or R⁵ and R⁶, together with the atom to which each is attached, form    a 3-8 membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a 3-8 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur; each of which is optionally    substituted;-   n is 0, 1, or 2; and-   p is 0 or 1.

In certain embodiments, X is O. In certain embodiments, X is S. Incertain embodiments, X is SO or SO₂. In certain embodiments, X is NR.

In certain embodiments, Y is O. In certain embodiments, Y is S. Incertain embodiments, Y is NR.

In certain embodiments, Z is O. In certain embodiments, Z is S. Incertain embodiments, Z is SO or SO₂. In certain embodiments, Z is N.

In certain embodiments, Ring A is a fused aryl. In certain embodiments,Ring A is a fused 3-8 membered saturated or partially unsaturatedcarbocyclic ring. In certain embodiments, Ring A is a fused 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, Ring A is a fused5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, Ring A is phenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, furanyl, furazanyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, piperazinyl, piperidinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, tetrahydrofuranyl, thiazolyl, thiophenyl, oxetanyl, orazetidinyl.

In certain embodiments, Ring A is phenyl.

In certain embodiments, R¹ is —OR, —SR, —SO₂R, —SOR, —C(O)R, —CO₂R,—C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂. In certainembodiments, R¹ is —OR, —SR, —SO₂R, or —SOR. In certain embodiments, R¹is —C(O)R, —CO₂R, or —C(O)N(R)₂. In certain embodiments, R¹ is —NRC(O)R,—NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂.

In certain embodiments, R¹ is —OR, and R is hydrogen.

In certain embodiments, R¹ is —OR, and R is C₁₋₆ aliphatic, aryl, a 3-8membered saturated or partially unsaturated carbocyclic ring, a 3-7membered heterocylic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R¹ is —OR, and R is C₁₋₆ aliphatic. In certainembodiments, R is methyl, ethyl, propyl, i-propyl, butyl, s-butyl,t-butyl, straight or branched pentyl, or straight or branched hexyl;each of which is optionally substituted. In certain embodiments, R ismethyl or or deuterated methyl. In certain embodiments, R is methyl.

In certain embodiments, R¹ is —OR, and R is aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In certain embodiments, R is phenyl, naphthyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl,[4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl,tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R¹ is —OR, and R² is aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, or a 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; each of which is optionallysubstituted.

In certain embodiments, R¹ is —OR, and R² is a 6-membered aryl ring, a3-membered carbocyclic ring, or a 5-6 membered monocyclic heteroarylring having 1-4 nitrogen atoms; each of which is optionally substituted.

In certain embodiments, R² is hydrogen.

In certain embodiments, R² is C₁₋₆ aliphatic. In certain embodiments, R²is C₁₋₆ aliphatic wherein the aliphatic group is a C₁₋₆ alkyl. Incertain embodiments, R² is methyl, ethyl, propyl, i-propyl, butyl,s-butyl, t-butyl, straight or branched pentyl, or straight or branchedhexyl; each of which is optionally substituted. In certain embodiments,R² is C₁₋₆ aliphatic wherein the aliphatic group is a C₁₋₆ alkenyl.

In certain embodiments, R² is aryl, a 3-8 membered saturated orpartially unsaturated carbocyclic ring, a 3-7 membered heterocylic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted.

In certain embodiments, R² is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R² is halogen, -haloalkyl, —OR, —SR, —CN, —NO₂,—SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R,or —N(R)₂.

In certain embodiments, R² is F, Cl, Br, I, or haloalkyl.

In certain embodiments, R² is —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R,—CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂. Incertain embodiments, R is C₁ 6 aliphatic, aryl, a 3-8 membered saturatedor partially unsaturated carbocyclic ring, a 3-7 membered heterocylicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted. In certain embodiments, R ismethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight orbranched pentyl, or straight or branched hexyl; each of which isoptionally substituted. In certain embodiments, R is methyl, ethyl, orpropyl; each of which is optionally substituted. In other embodiments, Ris phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl,[4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl,fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl,benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R² is

In certain embodiments, R³ is phenyl or naphthyl; each of which isoptionally substituted.

In certain embodiments, R³ is an optionally substituted phenyl. Incertain embodiments, R³ is phenyl substituted by —R, halogen,-haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂.

In certain embodiments, R³ is

In certain embodiments, each R⁴ is independently hydrogen.

In certain embodiments, each R⁴ is independently C₁₋₆ aliphatic, aryl, a3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7membered heterocylic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, each R⁴ is independently an optionallysubstituted C₁₋₆ aliphatic. In certain embodiments, each R⁴ isindependently an optionally substituted aryl. In certain embodiments,each R⁴ is independently an optionally substituted 3-8 memberedsaturated or partially unsaturated carbocyclic ring. In certainembodiments, each R⁴ is independently an optionally substituted 3-7membered heterocylic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In certain embodiments, each R⁴ isindependently an optionally substituted 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In certain embodiments, each R⁴ is independently halogen, -haloalkyl,—OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂.

In certain embodiments, R⁵ is C₁₋₆ aliphatic, SO₂R, —SOR, aryl, a 3-8membered saturated or partially unsaturated carbocyclic ring, a 3-7membered heterocylic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R⁵ is an optionally substituted C₁₋₆ aliphatic.In certain embodiments, R⁵ is an optionally substituted aryl. In certainembodiments, R⁵ is an optionally substituted 3-8 membered saturated orpartially unsaturated carbocyclic ring. In certain embodiments, R⁵ is anoptionally substituted 3-7 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, R⁵ is an optionally substituted 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In certain embodiments, R⁵ is C₁₋₆ aliphatic. In certain embodiments, R⁵is methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight orbranched pentyl, or straight or branched hexyl; each of which isoptionally substituted.

In certain embodiments, R⁵ is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R⁵ and R⁶, together with the atom to which eachis attached, form a 3-8 membered heterocylic 1 ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each of which is optionallysubstituted.

In certain embodiments, R⁵ is methyl, t-butyl,

In certain embodiments, Z is N. In certain embodiments, Z is N and R⁵,R⁶, and Z together with the atoms to which each is attached form anoptionally substituted 3-8 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, Z is N and the ring formed by Z, R⁵ and R⁶ isOH,

In certain embodiments, R⁶ is hydrogen.

In certain embodiments, R⁶ is C₁₋₆ aliphatic, SO₂R, —SOR, aryl, a 3-8membered saturated or partially unsaturated carbocyclic ring, a 3-7membered heterocylic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R⁶ is an optionally substituted C₁₋₆ aliphatic.In certain embodiments, R⁶ is an optionally substituted aryl. In certainembodiments, R⁶ is an optionally substituted 3-8 membered saturated orpartially unsaturated carbocyclic ring. In certain embodiments, R⁶ is anoptionally substituted 3-7 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, R⁶ is an optionally substituted 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In certain embodiments, R⁶ is C₁₋₆ aliphatic. In certain embodiments, R⁶is methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight orbranched pentyl, or straight or branched hexyl; each of which isoptionally substituted.

In certain embodiments, R⁶ is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R⁶ is hydrogen.

In certain embodiments, R⁶ is SO₂R or —SOR.

In certain embodiments, R⁶ is optionally substituted C₁₋₆ aliphatic or—SO₂R.

In certain embodiments, R⁶ is methyl, ethyl, t-butyl, or

In certain embodiments, n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2.

In certain embodiments, p is 0. In certain embodiments, p is 1.

In certain embodiments, each of R¹, R², R³, R⁴, R⁵, R⁶, X, Y, Z, n, andp is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-a,

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁵, R⁶, X, Y, Z, and p is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the present invention provides a compound offormula I-b,

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, R⁵, R⁶, Y, Z, n, and p is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the compound is of formula I-c:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁵, R⁶, Z, and p is as defined above and described in embodiments,classes and subclasses above and herein, singly or in combination.

In certain embodiments, the invention provides a compound of formulaI-d:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁵, and R⁶ is as defined above and described in embodiments, classesand subclasses above and herein, singly or in combination.

In other embodiments, the invention provides a compound of formula I-e:

or a pharmaceutically acceptable salt thereof, wherein each of R², R³,R⁵, and R⁶ is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In other embodiments, the invention provides a compound of formula I-f:

or a pharmaceutically acceptable salt thereof, wherein R² is aryl, a 3-8membered saturated or partially unsaturated carbocyclic ring, or a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each of which is optionallysubstituted; R³ is an optionally substituted phenyl; R⁵ is an optionallysubstituted C₁₋₆ aliphatic; R⁶ is an optionally substituted C₁₋₆aliphatic; or R⁵ and R⁶, together with the atom to which each isattached, form an optionally substituted 3-8 membered heterocylic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

In a second aspect, the present invention provides a compound of formulaII,

or a pharmaceutically acceptable salt thereof, wherein:

-   X is O, S, SO, SO₂, or NR;-   Y is O, S, or NR;-   Z is O, S, SO, SO₂, or N; wherein when Z is O, S, SO, or SO₂, then p    is 0;-   each R is independently hydrogen, C₁₋₆ aliphatic, aryl, a 3-8    membered saturated or partially unsaturated carbocyclic ring, a 3-7    membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur; each of which is    optionally substituted; or-   two R groups on the same atom are taken together with the atom to    which they are attached to form an aryl ring, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted;-   Ring A is a fused aryl, a fused 3-8 membered saturated or partially    unsaturated carbocyclic ring, a fused 3-7 membered heterocylic ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or a fused 5-6 membered monocyclic heteroaryl ring having    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur;-   R¹ is —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂,    —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂;-   R² is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR,    —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or    —N(R)₂;-   R³ is an optionally substituted 5-6 membered monocyclic heteroaryl    ring;-   each R⁴ is independently —R, halogen, -haloalkyl, —OR, —SR, —CN,    —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R,    —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂;-   R⁵ is C₁₋₆ aliphatic, —SO₂R, —SOR, aryl, a 3-8 membered saturated or    partially unsaturated carbocyclic ring, a 3-7 membered heterocylic    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur; each of which is optionally substituted;-   R⁶ is hydrogen, C₁₋₆ aliphatic, —SO₂R, —SOR, aryl, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted;-   or R⁵ and R⁶, together with the atom to which each is attached, form    a 3-8 membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a 3-8 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur; each of which is optionally    substituted;-   n is 0, 1, or 2; and-   p is 0 or 1.

In certain embodiments, X is O. In certain embodiments, X is S. Incertain embodiments, X is SO or SO₂. In certain embodiments, X is NR.

In certain embodiments, Y is O. In certain embodiments, Y is S. Incertain embodiments, Y is NR.

In certain embodiments, Z is O. In certain embodiments, Z is S. Incertain embodiments, Z is SO or SO₂. In certain embodiments, Z is N.

In certain embodiments, Ring A is a fused aryl. In certain embodiments,Ring A is a fused 3-8 membered saturated or partially unsaturatedcarbocyclic ring. In certain embodiments, Ring A is a fused 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In certain embodiments, Ring A is a fused5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, Ring A is phenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, furanyl, furazanyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, piperazinyl, piperidinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, tetrahydrofuranyl, thiazolyl, thiophenyl, oxetanyl, orazetidinyl.

In certain embodiments, Ring A is phenyl.

In certain embodiments, R¹ is —OR, —SR, —SO₂R, —SOR, —C(O)R, —CO₂R,—C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂. In certainembodiments, R¹ is —OR, —SR, —SO₂R, or —SOR. In certain embodiments, R¹is —C(O)R, —CO₂R, or —C(O)N(R)₂. In certain embodiments, R¹ is —NRC(O)R,—NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂.

In certain embodiments, R¹ is —OR, and R is hydrogen.

In certain embodiments, R¹ is —OR, and R is C₁₋₆ aliphatic, aryl, a 3-8membered saturated or partially unsaturated carbocyclic ring, a 3-7membered heterocylic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R¹ is —OR, and R is C₁₋₆ aliphatic. In certainembodiments, R is methyl, ethyl, propyl, i-propyl, butyl, s-butyl,t-butyl, straight or branched pentyl, or straight or branched hexyl;each of which is optionally substituted. In certain embodiments, R ismethyl.

In certain embodiments, R¹ is —OR, and R is aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In certain embodiments, R is phenyl, naphthyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl,[4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl,tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R¹ is —OR, and R² is OR, C₁₋₆ aliphatic, Aryl, a3-8 membered saturated or partially unsaturated carbocyclic ring, or a5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each of whichis optionally substituted.

In certain embodiments, R¹ is —OR, and R² is —OR, C₁₋₆ aliphatic, a6-membered aryl ring, or a 5-6 membered monocyclic heteroaryl ringhaving 1-4 nitrogen atoms; each of which is optionally substituted.

In certain embodiments, R² is hydrogen.

In certain embodiments, R² is C₁₋₆ aliphatic. In certain embodiments, R²is C₁₋₆ aliphatic wherein the aliphatic group is a C₁₋₆ alkyl. Incertain embodiments, R² is methyl, ethyl, propyl, i-propyl, butyl,s-butyl, t-butyl, straight or branched pentyl, or straight or branchedhexyl; each of which is optionally substituted. In certain embodiments,R² is methyl, ethyl, propyl, or i-propyl. In certain embodiments, R² isi-propyl. In certain embodiments, R² is C₁₋₆ aliphatic wherein thealiphatic group is a C₁₋₆ alkenyl.

In certain embodiments, R² is aryl, a 3-8 membered saturated orpartially unsaturated carbocyclic ring, a 3-7 membered heterocylic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted.

In certain embodiments, R² is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R² is halogen, -haloalkyl, —OR, —SR, —CN, —NO₂,—SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R,or —N(R)₂.

In certain embodiments, R² is F, Cl, Br, I, or haloalkyl.

In certain embodiments, R² is —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R,—CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂. Incertain embodiments, R is C₁ 6 aliphatic, aryl, a 3-8 membered saturatedor partially unsaturated carbocyclic ring, a 3-7 membered heterocylicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted. In certain embodiments, R ismethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight orbranched pentyl, or straight or branched hexyl; each of which isoptionally substituted. In other embodiments, R is phenyl, naphthyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl,[4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl,tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R² is

In certain embodiments, R³ is thiophenyl, furanyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, and pyrazinyl.

In certain embodiments, R³ is thiophenyl or pyridyl; each of which isoptionally substituted.

In certain embodiments, R³ is S or

In certain embodiments, each R⁴ is independently hydrogen.

In certain embodiments, each R⁴ is independently C₁₋₆ aliphatic, C₃₋₁₀aryl, a 3-8 membered saturated or partially unsaturated carbocyclicring, a 3-7 membered heterocylic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each of which is optionallysubstituted.

In certain embodiments, each R⁴ is independently an optionallysubstituted C₁₋₆ aliphatic. In certain embodiments, each R⁴ isindependently an optionally substituted aryl. In certain embodiments,each R⁴ is independently an optionally substituted 3-8 memberedsaturated or partially unsaturated carbocyclic ring. In certainembodiments, each R⁴ is independently an optionally substituted 3-7membered heterocylic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In certain embodiments, each R⁴ isindependently an optionally substituted 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In certain embodiments, each R⁴ is independently halogen, -haloalkyl,—OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂.

In certain embodiments, R⁵ is C₁₋₆ aliphatic, aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R⁵ is an optionally substituted C₁₋₆ aliphatic.In certain embodiments, R⁵ is an optionally substituted aryl. In certainembodiments, R⁵ is an optionally substituted 3-8 membered saturated orpartially unsaturated carbocyclic ring. In certain embodiments, R⁵ is anoptionally substituted 3-7 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, R⁵ is an optionally substituted 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In certain embodiments, R⁵ is C₁₋₆ aliphatic. In certain embodiments, R⁵is methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight orbranched pentyl, or straight or branched hexyl; each of which isoptionally substituted.

In certain embodiments, R⁵ is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R⁵ and R⁶, together with the atom to which eachis attached, form a 3-8 membered heterocylic 1 ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each of which is optionallysubstituted.

In certain embodiments, R⁵ is methyl, t-butyl,

In certain embodiments, Z is N. In certain embodiments, Z is N and R⁵,R⁶, and Z together with the atoms to which each is attached form anoptionally substituted 3-8 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, Z is N and and the ring formed by Z, R⁵ and R⁶is

In certain embodiments, R⁶ is hydrogen.

In certain embodiments, R⁶ is C₁₋₆ aliphatic, aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R⁶ is an optionally substituted C₁₋₆ aliphatic.In certain embodiments, R⁶ is an optionally substituted aryl. In certainembodiments, R⁶ is an optionally substituted 3-8 membered saturated orpartially unsaturated carbocyclic ring. In certain embodiments, R⁶ is anoptionally substituted 3-7 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Incertain embodiments, R⁶ is an optionally substituted 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In certain embodiments, R⁶ is C₁ aliphatic. In certain embodiments, R⁶is methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight orbranched pentyl, or straight or branched hexyl; each of which isoptionally substituted.

In certain embodiments, R⁶ is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R⁶ is hydrogen.

In certain embodiments, R⁶ is methyl or t-butyl.

In certain embodiments, n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2.

In certain embodiments, p is 0. In certain embodiments, p is 1.

In certain embodiments, each of R¹, R², R³, R⁴, R⁵, R⁶, X, Y, Z, n, andp is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula II-a,

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁵, R⁶, X, Y, Z, and p is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the present invention provides a compound offormula II-b,

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, R⁵, R⁶, Y, Z, n, and p is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the compound is of formula II-c:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁵, R⁶, Z, and p is as defined above and described in embodiments,classes and subclasses above and herein, singly or in combination.

In certain embodiments, the invention provides a compound of formulaII-d:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁵, and R⁶ is as defined above and described in embodiments, classesand subclasses above and herein, singly or in combination.

In other embodiments, the invention provides a compound of formula II-e:

or a pharmaceutically acceptable salt thereof, wherein each of R², R³,R⁵, and R⁶ is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In other embodiments, the invention provides a compound of formula II-f:

or a pharmaceutically acceptable salt thereof, wherein R² is C₁₋₆aliphatic, —OR, aryl, a 3-8 membered saturated or partially unsaturatedcarbocyclic ring, or a 5-6 membered monocyclic heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted; R³ is an optionally substitutedthiophenyl or pyridyl; R⁵ is an optionally substituted C₁₋₆ aliphatic;R⁶ is an optionally substituted C₁₋₆ aliphatic or —SO₂R; or R⁵ and R⁶,together with the atom to which each is attached, form an optionallysubstituted 3-8 membered heterocylic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, the invention provides a compound selected fromTable 1.

TABLE 1 Exemplary compounds of the invention.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

In some embodiments, the present invention provides a compound selectedfrom those depicted above, or a pharmaceutically acceptable saltthereof.

Various structural depictions may show a heteroatom without an attachedgroup, radical, charge, or counterion. Those of ordinary skill in theart are aware that such depictions are meant to indicate that theheteroatom is attached to hydrogen (e.g.,

is understood to be

In certain embodiments, the compounds of the invention were synthesizedin accordance with Schemes A-C below. More specific examples ofcompounds made utilizing Schemes A-C are provided in the Examples below.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably modulate FSHR, or a mutant thereof,in a biological sample or in a patient. In certain embodiments, theamount of compound in compositions of this invention is such that iseffective to measurably modulate FSHR, or a mutant thereof, in abiological sample or in a patient. In certain embodiments, a compositionof this invention is formulated for administration to a patient in needof such composition.

The term “patient” or “subject”, as used herein, means an animal,preferably a mammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat are used in the compositions of this invention include, but are notlimited to, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

Compositions of the present invention are administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention include aqueous or oleaginous suspension.These suspensions are formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation is also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that are employed are water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium.

For this purpose, any bland fixed oil employed includes synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents that arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms arealso be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention are orallyadministered in any orally acceptable dosage form. Exemplary oral dosageforms are capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents are optionally also added.

Alternatively, pharmaceutically acceptable compositions of thisinvention are administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention are alsoadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches are also used.

For topical applications, provided pharmaceutically acceptablecompositions are formulated in a suitable ointment containing the activecomponent suspended or dissolved in one or more carriers. Exemplarycarriers for topical administration of compounds of this are mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, provided pharmaceutically acceptable compositions can beformulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Pharmaceutically acceptable compositions of this invention areoptionally administered by nasal aerosol or inhalation. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and are prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or otherconventional solubilizing or dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that are optionallycombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, provided compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe compound can be administered to a patient receiving thesecompositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In certain embodiments, the invention provides a method forallosterically agonising FSHR, or a mutant thereof, in a positive mannerin a patient or in a biological sample comprising the step ofadministering to said patient or contacting said biological sample witha compound according to the invention.

In certain embodiments, the invention is directed to the use ofcompounds of the invention and/or physiologically acceptable saltsthereof, for modulating a FSH receptor, particularly in the presence ofFSH. The term “modulation” denotes any change in FSHR-mediated signaltransduction, which is based on the action of the specific inventivecompounds capable to interact with the FSHR target in such a manner thatmakes recognition, binding and activating possible. The compounds arecharacterized by such a high affinity to FSHR, which ensures a reliablebinding and preferably a positive allosteric modulation of FSHR. Incertain embodiments, the substances are mono-specific in order toguarantee an exclusive and directed recognition with the single FSHRtarget. In the context of the present invention, the term“recognition”—without being limited thereto—relates to any type ofinteraction between the specific compounds and the target, particularlycovalent or non-covalent binding or association, such as a covalentbond, hydrophobic/hydrophilic interactions, van der Waals forces, ionpairs, hydrogen bonds, ligand-receptor interactions, and the like. Suchassociation may also encompass the presence of other molecules such aspeptides, proteins or nucleotide sequences. The presentreceptor/ligand-interaction is characterized by high affinity, highselectivity and minimal or even lacking cross-reactivity to other targetmolecules to exclude unhealthy and harmful impacts to the treatedsubject.

In certain embodiments, the present invention relates to a method formodulating an FSH receptor, and in particular in a positive allostericmanner, wherein a system capable of expressing the FSH receptor iscontacted, in the presence of FSH, with at least one compound of formula(I) or formula (II) according to the invention and/or physiologicallyacceptable salts thereof, under conditions such that said FSH receptoris modulated. In certain embodiments, modulation is in a positiveallosteric manner. In certain embodiments, the system is a cellularsystem. In other embodiments, the system is an in-vitro translationwhich is based on the protein synthesis without living cells. Thecellular system is defined to be any subject provided that the subjectcomprises cells. Hence, the cellular system can be selected from thegroup of single cells, cell cultures, tissues, organs and animals. Incertain embodiments, the method for modulating an FSH receptor isperformed in-vitro. The prior teaching of the present specificationconcerning the compounds of formula (I) or formula (II), including anyembodiments thereof, is valid and applicable without restrictions to thecompounds according to formula (I) or formula (II) and their salts whenused in the method for modulating FSHR. The prior teaching of thepresent specification concerning the compounds of formula (I) or formula(II), including any embodiments thereof, is valid and applicable withoutrestrictions to the compounds according to formula (I) or formula (II)and their salts when used in the method for modulating FSHR.

In certain embodiments, the compounds according to the invention exhibitan advantageous biological activity, which is easily demonstrated incell culture-based assays, for example assays as described herein or inprior art (cf. e.g. WO 2002/09706, which is incorporated herein byreference). In such assays, the compounds according to the inventionpreferably exhibit and cause an agonistic effect. In certainembodiments, the compounds of the invention have an FSHR agonistactivity, as expressed by an EC₅₀ standard, of less than 5 μM. Incertain embodiments, less than 1 μM. In certain embodiments, less than0.5 μM. In certain embodiments, less than 0.1 μM. “EC₅₀” is theeffective concentration of a compound at which 50% of the maximalresponse of that obtained with FSH would be obtained.

As discussed herein, these signaling pathways are relevant for variousdiseases, including fertility disorders. Disorders/diseases treated bythe methods of the invention include but are not limited to,hypogonadotropic hypogonadism, Isolated idiopathic hypogonadotropichypogonadism, Kallmann syndrome, Idiopathic hypogonadotropichypogonadism, Craniopharyngiomas, Combined pituitary hormone deficiency,Fertile eunuch syndrome, Abnormal beta subunit of LH, Abnormal betasubunit of FSH, mass lesions, pituitary adenomas, cysts, metastaticcancer to the sella (breast in women, lung and prostate in men),Infiltrative lesions, Hemochromatosis, sarcoidosis, histiocytosis,lymphoma, Lymphocytic hypophysitis, Infections, Meningitis, Pituitaryapoplexy, Hyperprolactinemia, hypothyroidism, Intentional (iatrogenic)secondary hypogonadism, Empty sella, Pituitary infarction, Sheehansyndrome, Anorexia nervosa, Congenital adrenal hyperplasia, anddisorders related to GnRH deficiency. Accordingly, the compoundsaccording to the invention are useful in the prophylaxis and/ortreatment of diseases that are dependent on the said signaling pathwaysby interaction with one or more of the said signaling pathways. Thepresent invention therefore relates to compounds according to theinvention as modulators, preferably agonists, more preferably positiveallosteric modulators, of the signaling pathways described herein,preferably of the FSHR-mediated signaling pathway. The compounds of theinvention are supposed to bind to the intracellular receptor domainwithout a competitive interaction with FSH, but they act as anallosteric enhancer of FSH on its receptor. The non-competitiveinteraction refers to the nature of the agonist activity exhibited bythe compounds of the invention, wherein the compounds activate FSHRwithout substantially reducing the magnitude of binding of FSH to FSHR.

In certain embodiments, the invention is directed towards thestimulation of follicular development, ovulation induction, controlledovarial hyperstimulation, assisted reproductive technology, includingin-vitro fertilization, male hypogonadism and male infertility,including some types of failure of spermatogenesis.

It is another object of the invention to provide a method for treatingdiseases that are caused, mediated and/or propagated by FSHR activity,wherein at least one compound of formula (I) or formula (II) accordingto the invention and/or physiologically acceptable salts thereof isadministered to a mammal in need of such treatment. In certainembodiments, the invention provides a method for treating fertilitydisorders, wherein at least one compound of formula (I) or formula (II)according to the invention and/or physiologically acceptable saltsthereof is administered to a mammal in need of such treatment. Incertain embodiments, the compound is administered in an effective amountas defined above. In certain embodiments, the treatment is an oraladministration.

In certain embodiments, the method of treatment aims to achieveovulation induction and/or controlled ovarian hyperstimulation. In stillanother embodiment, the method of treatment forms the basis for a methodfor in-vitro fertilization comprising the steps of: (a) treating amammal according to the method of treatment as described above, (b)collecting ova from said mammal, (c) fertilizing said ova, and (d)implanting said fertilized ova into a host mammal. The host mammal canbe either the treated mammal (i.e. the patient) or a surrogate. Theprior teaching of the invention and its embodiments is valid andapplicable without restrictions to the methods of treatment ifexpedient.

The method of the invention can be performed either in-vitro or in-vivo.The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be particularly determined by in-vitrotests, whether in the course of research or clinical application.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to modulate FSHR activity, usuallybetween about one hour and one week. In-vitro treatment can be carriedout using cultivated cells from a biopsy sample or cell line. In apreferred aspect of the invention, a follicle cell is stimulated formaturation. The viable cells remaining after the treatment are countedand further processed.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models and models of transgenic animals. For thedetermination of certain stages in the signal transduction cascade,interacting compounds can be utilized in order to modulate the signal.The compounds according to the invention can also be used as reagentsfor testing FSHR-dependent signal transduction pathways in animalsand/or cell culture models or in the clinical diseases mentioned in thisapplication.

The use according to the previous paragraphs of the specification may beeither performed in-vitro or in-vivo models. The modulation can bemonitored by the techniques described in the course of the presentspecification. In certain embodiments, the in-vitro use is preferablyapplied to samples of humans suffering from fertility disorders. Testingof several specific compounds and/or derivatives thereof makes theselection of that active ingredient possible that is best suited for thetreatment of the human subject. The in-vivo dose rate of the chosenderivative is advantageously pre-adjusted to the FSHR susceptibilityand/or severity of disease of the respective subject with regard to thein-vitro data. Therefore, the therapeutic efficacy is remarkablyenhanced. Moreover, the subsequent teaching of the present specificationconcerning the use of the compounds according to formula (I) or formula(II) and its derivatives for the production of a medicament for theprophylactic or therapeutic treatment and/or monitoring is considered asvalid and applicable without restrictions to the use of the compound forthe modulation of FSHR activity if expedient.

The invention also relates to the use of compounds according to formula(I) or formula (II) and/or physiologically acceptable salts thereof forthe prophylactic or therapeutic treatment and/or monitoring of diseasesthat are caused, mediated and/or propagated by FSHR activity.Furthermore, the invention relates to the use of compounds according toformula (I) or formula (II) and/or physiologically acceptable saltsthereof for the production of a medicament for the prophylactic ortherapeutic treatment and/or monitoring of diseases that are caused,mediated and/or propagated by FSHR activity. In certain embodiments, theinvention provides the use of a compound according to formula (I) orformula (II) or formula (II) or physiologically acceptable saltsthereof, for the production of a medicament for the prophylactic ortherapeutic treatment of a FSHR-mediated disorder.

Compounds of formula (I) or formula (II) and/or a physiologicallyacceptable salt thereof can furthermore be employed as intermediate forthe preparation of further medicament active ingredients. The medicamentis preferably prepared in a non-chemical manner, e.g. by combining theactive ingredient with at least one solid, fluid and/or semi-fluidcarrier or excipient, and optionally in conjunction with a single ormore other active substances in an appropriate dosage form.

Another object of the present invention are compounds of formula (I) orformula (II) according to the invention and/or physiologicallyacceptable salts thereof for use in the prophylactic or therapeutictreatment and/or monitoring of diseases that are caused, mediated and/orpropagated by FSHR activity. Another preferred object of the inventionconcerns compounds of formula (I) or formula (II) according to theinvention and/or physiologically acceptable salts thereof for use in theprophylactic or therapeutic treatment and/or monitoring of fertilitydisorders. The prior teaching of the present specification concerningthe compounds of formula (I) or formula (II), including any preferredembodiment thereof, is valid and applicable without restrictions to thecompounds according to formula (I) or formula (II) and their salts foruse in the prophylactic or therapeutic treatment and/or monitoring offertility disorders.

The compounds of formula (I) or formula (II) according to the inventioncan be administered before or following an onset of disease once orseveral times acting as therapy. The aforementioned compounds andmedical products of the inventive use are particularly used for thetherapeutic treatment. A therapeutically relevant effect relieves tosome extent one or more symptoms of a disorder, or returns to normality,either partially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition. Monitoring is considered as a kind of treatment provided thatthe compounds are administered in distinct intervals, e.g. in order tobooster the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The methods of the invention can also be used toreducing the likelihood of developing a disorder or even prevent theinitiation of disorders associated with FSHR activity in advance or totreat the arising and continuing symptoms. In certain embodiments, thedisorders are fertility disorders.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously passed disease.

The invention furthermore relates to a medicament comprising at leastone compound according to the invention and/or pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. In certain embodiments, the inventionrelates to a medicament comprising at least one compound according tothe invention and/or physiologically acceptable salts thereof.

A “medicament” in the meaning of the invention is any agent in the fieldof medicine, which comprises one or more compounds of formula (I) orformula (II) or preparations thereof (e.g. a pharmaceutical compositionor pharmaceutical formulation) and can be used in prophylaxis, therapy,follow-up or aftercare of patients who suffer from diseases, which areassociated with FSHR activity, in such a way that a pathogenicmodification of their overall condition or of the condition ofparticular regions of the organism could establish at least temporarily.

In various embodiments, the active ingredient may be administered aloneor in combination with other treatments. A synergistic effect may beachieved by using more than one compound in the pharmaceuticalcomposition, i.e. the compound of formula (I) or formula (II) iscombined with at least another agent as active ingredient, which iseither another compound of formula (I) or formula (II) or a compound ofdifferent structural scaffold. The active ingredients can be used eithersimultaneously or sequentially. The present compounds are suitable forcombination with known fertility-inducing agents. In certainembodiments, the other active pharmaceutical ingredient is selected fromthe group of FSH, α-FSH (Gonal F), β-FSH, LH, hMG and2-(4-(2-chloro-1,2-diphenylethenyl)-phenoxy)-N,N-diethyl-ethanaminecitrate (Chlomifene citrate). Further ovulation adjuncts are known tothose of skill in the art (cf. e.g. WO 2002/09706, which is incorporatedherein by reference) and are useful with the compounds of the presentinvention.

In another aspect, the invention provides for a kit consisting ofseparate packs of an effective amount of a compound according to theinvention and/or pharmaceutically acceptable salts, derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally, an effective amount of a further activeingredient. The kit comprises suitable containers, such as boxes,individual bottles, bags or ampoules. The kit may, for example, compriseseparate ampoules, each containing an effective amount of a compoundaccording to the invention and/or pharmaceutically acceptable salts,derivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and an effective amount of a further activeingredient in dissolved or lyophilized form.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment is administered afterone or more symptoms have developed. In other embodiments, treatment isadministered in the absence of symptoms. For example, treatment isadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment is also continued aftersymptoms have resolved, for example to prevent or delay theirrecurrence.

The compounds and compositions, according to the method of the presentinvention, are administered using any amount and any route ofadministration effective for treating or lessening the severity of adisorder provided above. The exact amount required will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention are administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 100mg/kg and preferably from about 1 mg/kg to about 50 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms optionally contain inert diluents commonly usedin the art such as, for example, water or other solvents, solubilizingagents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions are formulated according to the known art usingsuitable dispersing or wetting agents and suspending agents. The sterileinjectable preparation are also a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This is accomplished by the useof a liquid suspension of crystalline or amorphous material with poorwater solubility. The rate of absorption of the compound then dependsupon its rate of dissolution that, in turn, may depend upon crystal sizeand crystalline form. Alternatively, delayed absorption of aparenterally administered compound form is accomplished by dissolving orsuspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form also optionally comprises buffering agents.

Solid compositions of a similar type are also employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype are also employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms optionally also comprisebuffering agents. They optionally contain opacifying agents and can alsobe of a composition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as required. Ophthalmicformulation, ear drops, and eye drops are also contemplated as beingwithin the scope of this invention. Additionally, the present inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms can be made by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofallosterically modulating FSHR activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofallosterically modulating FSHR, or a mutant thereof, activity in abiological sample in a positive manner, comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

The compounds of the invention are strong and selective modulators ofthe FSH receptor. Their selectivity to the FSH receptor is 3 to 10-foldover the LH receptor and even 10 to 100-fold over the TSH receptor whilethe EC₅₀ or IC₅₀ amounts to more than 10 μM on unrelated Gprotein-coupled receptors (GPCR) or non-GPCR targets. The currentinvention comprises the use of the compounds of the invention in theregulation and/or modulation of the FSHR signal cascade, which can beadvantageously applied as research tool, for diagnosis and/or intreatment of any disorder arising from FSHR signaling.

For example, the compounds of the invention are useful in-vitro asunique tools for understanding the biological role of FSH, including theevaluation of the many factors thought to influence, and be influencedby, the production of FSH and the interaction of FSH with the FSHR (e.g.the mechanism of FSH signal transduction/receptor activation). Thepresent compounds are also useful in the development of other compoundsthat interact with FSHR since the present compounds provide importantstructure-activity relationship (SAR) information that facilitate thatdevelopment. Compounds of the present invention that bind to FSHR can beused as reagents for detecting FSHR on living cells, fixed cells, inbiological fluids, in tissue homogenates, in purified, naturalbiological materials, etc. For example, by labeling such compounds, onecan identify cells having FSHR on their surfaces. In addition, based ontheir ability to bind FSHR, compounds of the present invention can beused in in-situ staining, FACS (fluorescence-activated cell sorting),western blotting, ELISA (enzyme-linked immunoadsorptive assay), etc.,receptor purification, or in purifying cells expressing FSHR on the cellsurface or inside permeabilized cells.

The compounds of the invention can also be utilized as commercialresearch reagents for various medical research and diagnostic uses. Suchuses can include but are not limited to: use as a calibration standardfor quantifying the activities of candidate FSH agonists in a variety offunctional assays; use as blocking reagents in random compoundscreening, i.e. in looking for new families of FSH receptor ligands, thecompounds can be used to block recovery of the presently claimed FSHcompounds; use in the co-crystallization with FSHR receptor, i.e. thecompounds of the present invention will allow formation of crystals ofthe compound bound to FSHR, enabling the determination ofreceptor/compound structure by x-ray crystallography; other research anddiagnostic applications, wherein FSHR is preferably activated or suchactivation is conveniently calibrated against a known quantity of an FSHagonist, etc.; use in assays as probes for determining the expression ofFSHR on the surface of cells; and developing assays for detectingcompounds which bind to the same site as the FSHR binding ligands.

The compounds of the invention can be applied either themselves and/orin combination with physical measurements for diagnostics of treatmenteffectiveness. Pharmaceutical compositions containing said compounds andthe use of said compounds to treat FSHR-mediated conditions is apromising, novel approach for a broad spectrum of therapies causing adirect and immediate improvement in the state of health, whether inhuman or animal. The impact is of special benefit to efficiently combatinfertility, either alone or in combination with otherfertility-inducing treatments. In particular, the compounds of theinvention potentiate the native FSH effect for both ovulation inductionand assisted reproductive technology. The orally bioavailable and activenew chemical entities of the invention improve convenience for patientsand compliance for physicians.

The compounds of the invention are active in the primary screen (CHOwith or without FSH), selective in secondary screen (no or low activityagainst TSHR and LHR) and potent in the granulosa cell estrodiol assay.Neither hERG nor any toxic effects could be observed in-vitro.

In certain embodiments, the invention provides a method for in-vitrofertilization comprising the steps of:

-   (a) treating a mammal according to the method as described above,-   (b) collecting ova from said mammal,-   (c) fertilizing said ova, and-   (d) implanting said fertilized ova into a host mammal.

The compounds of formula (I) or formula (II), their salts, isomers,tautomers, enantiomeric forms, diastereomers, racemates, derivatives,prodrugs and/or metabolites are characterized by a high specificity andstability, low manufacturing costs and convenient handling. Thesefeatures form the basis for a reproducible action, wherein the lack ofcross-reactivity is included, and for a reliable and safe interactionwith the target structure.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Modulation of FSHR, or a mutant thereof, activity in a biological sampleis useful for a variety of purposes that are known to one of skill inthe art. Examples of such purposes include, but are not limited to,blood transfusion, organ transplantation, biological specimen storage,and biological assays.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Compound numbers utilized in the Examples below correspond to compoundnumbers set forth supra.

¹H NMR was recorded on a Bruker 400 MHz spectrometer, using the residualsignal of deuterated solvent as an internal reference. Chemical shifts(δ) are reported in ppm relative to the residual solvent signal (δ=2.49ppm for ¹H NMR in DMSO-d₆). ¹H NMR data are reported as follows:chemical shift (multiplicity, coupling constants, and number ofhydrogens). Multiplicity is abbreviated as follows: s (singlet), d(doublet), t (triplet), q (quartet), m (multiplet), br (broad).

LC-MS analysis was performed under the following conditions: Method: A:0.1% TFA in H₂O, B:0.1% TFA in ACN; Run time: 6.5 min; Flow Rate: 1.0mL/min; Gradient: 5-95% B in 4.5 min, wavelengths 254 and 215 nM;Column: Waters Sunfire C18, 3.0×50 mm, 3.5 um, positive mode; Mass Scan:100-900 Da.

Example 1:N-tert-butyl-1-(3,5-dichlorophenyl)-8-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 1)

Step 1: Ethyl8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate

To a solution of (Z)-ethyl2-(6-bromo-7-methoxy-4-oxochroman-3-ylidene)-2-hydroxyacetate (500 mg,1.4 mmol) in a mixture of t-BuOH (30 mL) and acetic acid (420 mg, 7mmol) was added (3,5-dichlorophenyl)hydrazine hydrochloride (290 mg, 1.4mmol) at RT under nitrogen. The reaction mixture was stirred at 90° C.for 4 h. The reaction mixture was concentrated under high vacuum. Theresidue was dissolved with ethyl acetate (40 mL), washed with water (10mL), brine (20 mL), dried over sodium sulphate and concentrated undervacuum. The crude product was purified by column chromatography usingpet ether/ethyl acetate as an eluent to afford the titled compound (600mg, 75%) as a pale yellow solid.

Step 2:8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid

To a solution of ethyl8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate(100 mg, 0.2 mmol) in a mixture of THF (10 mL) and H₂O (10 mL) was addedLiOH.H₂O (17 mg, 0.4 mmol) at RT. The reaction mixture was stirred at RTfor 4 h. The reaction mixture was evaporated and acidified with asolution of 1.5N HCl. The solid was filtered and dried to afford thedesired compound (80 mg, 89%) as an off-white solid.

Step 3:8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution of8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (500 mg, 0.11 mmol) in DMF (10 mL) was added N-tert-butyl methylamine (140 mg, 1.6 mmol), HATU (420 mg, 1.1 mmol) anddiisopropylethylamine (280 mg, 2.13 mmol) at RT under nitrogen. Thereaction mixture was stirred at RT for 3 h. The reaction mixture wasquenched to sodium bicarbonate (10 mL, 10%), and extracted with EtOAc(2×50 mL). The combined organic layer was washed with NaHCO₃ solution(30 mL, 10% solution), brine (30 mL) and dried over anhydrous sodiumsulphate. The solvent was removed under vacuum; the crude product waspurified by column chromatography by using pet ether and ethyl acetate(9:1) as an eluent to afford the desired compound (40 mg, 67%) as awhite solid.

Step 4: Methyl2-(4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)-1H-pyrazol-1-yl)acetate

To a solution of8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(200 mg, 0.37 mmol) in dioxane (6 mL) was added methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate(150 mg, 0.56 mmol), PdCl₂(dppf) (54 mg, 0.07 mmol) and KF (43 mg, 0.74mmol) at RT under nitrogen. The reaction mixture was degassed withnitrogen for 20 min and water (4 mL) was added at RT. The reactionmixture was stirred at 90° C. for 1 h under MW conditions. The reactionmixture was filtered through celite and washed with DCM (50 mL). Thefiltrate was concentrated under vacuum; the crude product was washedwith water (10 ml), brine (10 mL) and dried over sodium sulphate. Theorganic solvent was removed under vacuum; the crude product was purifiedby column chromatograph using pet ether: ethyl acetate as an eluent toafford the desired compound (90 mg, 51%) as an off-white solid.

Step 5:N-tert-butyl-1-(3,5-dichlorophenyl)-8-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 1)

To a stirred solution of methyl2-(4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)-1H-pyrazol-1-yl)acetate(200 mg, 0.33 mmol) in MeOH (20 ml) and THF (20 ml) was added NaBH₄ (50mg, 1.32 mmol) at RT for 0.5 h. Water (10 ml) was added to the mixtureand extracted by DCM (100 ml), then dried over sodium sulphate. Theorganic solvent was removed under vacuum; the crude product was purifiedby column chromatograph using pet ether: ethyl acetate as an eluent toafford the desired compound (100 mg, 65%) as a white solid. ¹H NMR (400MHz, CDCl₃): 7.72 (s, 1H), 7.56 (s, 3H), 7.49 (s, 1H), 7.09 (s, 1H),6.70 (s, 1H), 5.47 (s, 2H), 4.26 (t, 2H), 4.03 (d, 2H), 3.92 (s, 3H),3.28 (s, 3H), 1.54 (s, 9H).

Example 2:8-(1-(2-amino-2-oxoethyl)-1H-pyrazol-4-yl)-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 2)

A mixture of methyl2-(4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)-1H-pyrazol-1-yl)acetate(100 mg, 0.066 mmol) and NH₃ in MeOH (12 ml) was heated to 60° C. for 2h. The solvents were removed to provide crude product, which waspurified by preparative HPLC to provide the desired product (60 mg, 66%)as a white solid. ¹H NMR (400 MHz, CDCl₃): 7.79 (s, 1H), 7.57 (s, 4H),7.11 (s, 1H), 6.71 (s, 1H), 5.48 (s, 2H), 4.83 (s, 2H), 3.93 (s, 3H),3.28 (s, 3H), 1.54 (s, 9H).

The following compounds were prepared using procedures analogous tothose disclosed in Scheme 1.

Boronic acid Amine Starting Starting Compound material material LC/MSNMR

m/z: 555 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ : 8.14 (d, J = 4.4 Hz, 1H),7.71-7.66 (m, 1H), 7.49 (d, J = 1.6 Hz, 2H), 7.44-7.43 (m, 1H),7.20-7.17 (m, 1H), 6.86 (s, 1H), 6.72 (s, 1H), 5.48 (s, 2H), 3.81 (s,3H), 3.26 (s, 3H), 1.52 (s, 9H). N-tert-butyl-1-(3,5-dichlorophenyl)-8-(2- fluoropyridin-3-yl)-7- methoxy-N-methyl-1,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide Compound 3

m/z: 540 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.62 (s, 1H), 7.53 (d, J =2.4 Hz, 2H), 7.48 (t, J = 2.0 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 6.66(s, 1H), 6.55 (d, J = 2.4 Hz, 1H), 5.45 (s, 2H), 3.88 (s, 3H), 3.86 (s,3H), 3.26 (s, 3H), 1.52 (s, 9H). N-tert-butyl-1-(3,5- dichlorophenyl)-7-methoxy-N-methyl-8-(1- methyl-1H-pyrazol-3-yl)- 1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 4

  4-{[1-(3,5-

m/z: 600 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.62 (s, 1H), 7.52 (m, 3H),7.31 (d, J = 2.0 Hz, 1H), 6.66 (s, 1H), 6.56 (d, J = 2.4 Hz, 1H), 5.46(s, 2H), 4.53-4.32 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.61-3.54 (m,1H), 3.14-3.04 (m, 2H), 2.85-2.80 (m, 1H), 1.57 (s, 6H).dichlorophenyl)-7- methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1H,4H-chromeno[4,3-c]pyrazol- 3-yl]carbonyl}-3,3- dimethyl-1$1{circumflex over( )}{4},4- thiomorpholin-1-one Compound 5

  (1-(3,5-

m/z: 615 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.16-8.15 (m, 1H), 7.71-7.66(m, 1H), 7.48 (s, 3H), 7.21-7.18 (m, 1H), 6.86 (s, 1H), 6.73 (s, 1H),5.48 (s, 2H), 4.52-4.32 (m, 2H), 3.82 (s, 3H), 3.60-3.52 (m, 1H),3.15-3.05 (m, 2H), 2.86-2.80 (m, 1H), 1.58 (s, 6H).dichlorophenyl)-8-(2- fluoropyridin-3-yl)-7- methoxy-1H,4H-chromeno[4,3- c]pyrazol-3-yl)(S- oxo-3,3- dimethylthiomorpholino)methanone Compound 6

  (1-(3,5-dichlorophenyl)- 7-methoxy-8-(1-methyl- 1H-pyrazol-3-yl)-1,4-

m/z: 582 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.62 (s, 1H), 7.53-7.52 (M,2H), 7.48- 7.47 (M, 1H), 7.31 (d, J = 2.0 Hz, 1H), 6.66 (s, 1H), 6.55(d, J = 1.6 Hz, 1H), 5.48-5.40 (m, 2H), 4.23- 4.17 (m, 1H), 4.10-4.04(m, 1H), 3.88 (s, sH), 3.87 (s, sH), 3.66-3.59 (m, 1H), 2.19-2.13 (s,1H), 1.91-1.72 (m, 2H), 1.46 (d, J = 4.4 Hz, 1H), 1.56 (s, 6H).dihydrochromeno[4,3- c]pyrazol-3-yl)(4- hydroxy-2,2-dimethylpiperidin-1- yl)methanone Compound 7

m/z: 562 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.76-8.74 (m, 2H), 7.98-7.97(m, 1H), 7.52 (m, 3H), 6.90 (s, 1H), 6.74 (s, 1H), 5.51 (s, 2H), 3.85(s, 3H), 3.27 (s, 3H), 1.52 (s, 9H). N-tert-butyl-8-(5-cyanopyridin-3-yl)-1-(3,5- dichlorophenyl)-7- methoxy-N-methyl-1,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide Compound 8

m/z: 568 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.59 (s, 1H), 7.51-7.48 (m,3H), 7.31 (d, J = 2.0 Hz, 1H), 6.66 (s, 1H), 6.55 (d, J = 2.0 Hz, 1H),5.45 (s, 2H), 4.07-4.04 (m, 2H), 3.88- 3.94 (m, 8H), 3.49 (s, 2H), 1.53(s, 6H). (1-(3,5-dichlorophenyl)- 7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1,4- dihydrochromeno[4,3- c]pyrazol-3-yl)(3,3-dimethylmorpholino) methanone Compound 9

  (1-(3,5-dichlorophenyl)-7- methoxy-8-(pyridin-2-yl)-1,4-dihydrochromeno[4,3-

m/z: 579 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J = 4.4 Hz, 1H),7.72 (d, J = 8.0 Hz, 1H), 7.66-7.62 (m, 1H), 7.57 (s, 1H), 7.52 (d, J =2.0 Hz, 2H), 7.44 (t, J = 2.0 Hz, 1H), 7.15-7.12 (m, 1H), 6.69 (s, 1H),5.51-5.43 (m, 2H), 4.24- 4.17 (m, 1H), 4.13-4.07 (m, 2H), 3.86 (s, 3H),3.67-3.60 (m, 1H), 2.19- 2.12 (m, 1H), 1.92-1.72 (m, 2H), 1.53 (s, 6H).c]pyrazol-3-yl)(4- hydroxy-2,2- dimethylpiperidin-1- yl)methanoneCompound 10

m/z: 565 [M + H]⁺ ¹H NMR (400 MHz, MeOD) δ 8.72 (s, 1H), 8.43 (t, J =7.6 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.71 (s, 3H), 7.27 (s, 1H), 6.97(s, 1H), 5.53 (s, 2H), 4.02 (t, J = 5.2 Hz, 2H), 3.97 (s, 3H), 3.85 (t,J = 4.8 Hz, 2H), 3.53 (s, 2H), 1.53 (s, 6H). (1-(3,5-dichlorophenyl)-7-methoxy-8-(pyridin-2- yl)-1,4- dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3- dimethylmorpholino) methanone Compound 11

m/z: 590 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.76-8.73 (m, 2H), 7.97 (t,J = 2.0 Hz, 1H), 7.54-7.51 (m, 3H), 6.88 (s, 1H), 6.74 (s, 1H), 5.51 (s,2H), 4.08-4.06 (m, 2H), 3.86 (m, 5H), 3.50 (s, 2H), 1.53 (s, 6H).5-(1-(3,5-dichlorophenyl)- 3-(3,3- dimethylmorpholine-4-carbonyl)-7-methoxy-1,4- dihydrochromeno[4,3- c]pyrazol-8-yl)nicotinonitrile Compound 12

m/z: 616 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.61 (s, 1H), 7.52-7.50 (m,3H), 7.31 (d, J = 2.0 Hz, 1H), 6.66 (s, 1H), 6.56 (d, J = 2.0 Hz, 1H),5.46 (s, 2H), 4.45 (t, J = 5.2 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.42(t, J = 5.6 Hz, 2H), 3.21 (s, 2H), 1.80 (s, 6H). 4-{[1-(3,5-dichlorophenyl)-7- methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1H,4H-chromeno[4,3-c]pyrazol- 3-yl]carbonyl}-3,3- dimethyl-1l{6},4-thiomorpholine-1,1-dione Compound 13

m/z: 562 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.63-8.62 (m, 1H), 7.66-7.64(m, 1H), 7.52-7.49 (m, 3H), 7.42- 7.41 (m, 1H), 6.82 (s, 1H), 6.75 (s,1H), 5.52 (s, 2H), 3.85 (s, 3H), 3.25 (s, 3H), 1.52 (s, 9H).N-tert-butyl-8-(2- cyanopyridin-3-yl)-1-(3,5- dichlorophenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 14

m/z: 541 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.50 (t, J =2.0 Hz, 1H), 7.46 (d, J = 1.6 Hz, 2H), 6.69 (d, J = 9.2 Hz, 2H), 5.46(s, 2H), 3.83 (s, 3H), 3.25 (s, 3H), 2.24 (s, 3H), 1.52 (s, 9H).N-tert-butyl-1-(3,5- dichlorophenyl)-7- methoxy-N-methyl-8-(5-methylisoxazol-4-yl)-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 15

m/z: 552 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, J = 2.0 Hz, 1H),7.52 (d, J = 2.4 Hz, 2H), 7.48-7.45 (m, 2H), 6.85 (s, 1H), 6.69 (s, 1H),6.50-6.48 (m, 1H), 5.44 (s, 2H), 3.81 (s, 3H), 3.26 (s, 3H), 1.52 (s,9H). 8-(6-aminopyridin-3-yl)- N-tert-butyl-1-(3,5- dichlorophenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 16

m/z: 566 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J = 1.6 Hz, 1H),7.52 (d, J = 1.6 Hz, 2H), 7.47 (m, 1H), 7.27 (s, 1H), 6.83 (s, 1H), 6.69(s, 1H), 5.44 (s, 2H), 3.81 (s, 3H), 3.26 (s, 3H), 2.15 (s, 3H), 1.52(s, 9H). 8-(6-amino-5- methylpyridin-3-yl)-N- tert-butyl-1-(3,5-dichlorophenyl)-7- methoxy-N-methyl-1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 17

m/z: 561 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.66 (t, J = 1.6 Hz, 1H),7.60-7.51 (m, 4H), 7.50 (t, J = 2.0 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H),6.88 (s, 1H), 6.71 (s, 1H), 5.48 (s, 2H), 3.83 (s, 3H), 3.27 (s, 3H),1.52 (s, 9H). N-tert-butyl-8-(3- cyanophenyl)-1-(3,5- dichlorophenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 18

m/z: 579 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.58-7.54 (m, 1H), 7.50-7.46(m, 3H), 7.44 (t, J = 2.0, 1H), 7.24 (s, 1H), 6.82 (s, 1H), 6.72 (s,1H), 5.49 (s, 2H), 3.81 (s, 3H), 3.26 (s, 3H), 1.52 (s, 9H).N-tert-butyl-8-(3-cyano-2- fluorophenyl)-1-(3,5- dichlorophenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 19

m/z: 552 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.01-7.99 (m, 2H), 7.53 (d,J = 2.0 Hz, 2H), 7.48 (d, J = 2.0 Hz, 1H), 6.98-6.97 (m, 1H), 6.90 (s,1H), 6.70 (s, 1H), 5.46 (s, 2H), 3.82 (s, 3H), 3.26 (s, 3H), 1.52 (s,9H). 8-(5-aminopyridin-3-yl)- N-tert-butyl-1-(3,5- dichlorophenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 20

m/z: 562 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.84 (s, 1H), 8.74 (d, J =5.2 Hz, 1H), 7.50 (d, J = 2.0 Hz, 2H), 7.45 (t, J = 2.0 Hz, 1H),7.24-7.22 (m, 1H), 6.83 (s, 1H), 6.75 (s, 1H), 5.53 (s, 2H), 3.87 (s,3H), 3.26 (s, 3H), 1.52 (s, 9H). N-tert-butyl-8-(2-cyanopyridin-4-yl)-1-(3,5- dichlorophenyl)-7- methoxy-N-methyl-1,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide Compound 21

m/z: 552 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 2.0 Hz, 2H),7.45 (t, J = 2.0 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.94-6.83 (m, 3H),6.78-6.75 (m, 1H), 6.68 (s, 1H), 5.43 (s, 2H), 3.80 (s, 3H), 3.25 (s,3H), 1.52 (s, 9H). N-tert-butyl-1-(3,5- dichlorophenyl)-8-(3-hydroxyphenyl)-7- methoxy-N-methyl-1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 22

m/z: 567 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.48 (dd, J = 8.8, 2.0 Hz,2H), 7.66- 7.65 (m, 1H), 7.47 (d, J = 1.6 Hz, 3H), 6.87 (s, 1H), 6.71(s, 1H), 5.46 (s, 2H), 4.74 (s, 2H), 3.82 (s, 3H), 3.26 (s, 3H), 1.52(s, 9H). N-tert-butyl-1-(3,5- dichlorophenyl)-8-(5-(hydroxymethyl)pyridin- 3-yl)-7-methoxy-N- methyl-1,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide Compound 23

m/z: 595 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.60-8.47 (m, 2H), 7.65 (s,1H), 7.50 (dd, J = 5.2, 1.7 Hz, 3H), 6.87 (s, 1H), 6.73 (s, 1H), 5.48(s, 2H), 4.75 (s, 2H), 4.06 (d, J = 5.3 Hz, 2H), 3.94-3.72 (m, 5H), 3.50(s, 2H), 1.53 (s, 6H). (1-(3,5-dichlorophenyl)- 8-(5-(hydroxymethyl)pyridin- 3-yl)-7-methoxy-1,4- dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3- dimethylmorpholino) methanone Compound 24

m/z: 579 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.64-7.48 (m, 3H), 7.42 (t,J = 1.8 Hz, 1H), 7.20-7.04 (m, 2H), 6.82 (s, 1H), 6.73 (s, 1H), 5.50 (s,2H), 3.86 (s, 3H), 3.25 (s, 3H), 1.52 (s, 9H).N-tert-butyl-8-(2-cyano-3- fluorophenyl)-1-(3,5- dichlorophenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 25

m/z: 562 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.70 (s, 1H), 8.12 (s, 1H),7.75 (s, 1H), 7.51 (d, J = 14.6 Hz, 3H), 7.33 (d, J = 4.8 Hz, 1H), 6.70(s, 1H), 5.52 (s, 2H), 3.92 (s, 3H), 3.27 (s, 3H), 1.52 (s, 9H).N-tert-butyl-8-(4- cyanopyridin-2-yl)-1-(3,5- dichlorophenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 26

  N-tert-butyl-1-(3-chloro-

m/z: 524 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.61 (s, 1H), 7.45-7.44 (m,1H), 7.30 (d, J = 2.4 Hz, 1H),7.25- 7.22 (m, 1H), 7.21-7.20 (m, 1H),6.66 (s, 1H), 6.55 (d, J = 2.4 Hz, 1H), 5.46 (s, 2H), 3.88 (s, 3H), 3.85(s, 3H), 3.26 (s, 3H), 1.51 (s, 9H). 5-fluorophenyl)-7-methoxy-N-methyl-8-(1- methyl-1H-pyrazol-3-yl)- 1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 27

m/z: 574 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.73 (dd, J = 22.3, 2.0 Hz,2H), 7.97 (t, J = 2.0 Hz, 1H), 7.40 (s, 1H), 7.29-7.28 (m, 1H),7.24-7.23 (m, 1H), 6.87 (s, 1H), 6.74 (s, 1H), 5.51 (s, 2H), 4.07 (t, J= 5.6 Hz, 2H), 3.87-3.85 (m, 5H), 3.50 (s, 2H), 1.53 (s, 6H).5-(1-(3-chloro-5- fluorophenyl)-3-(3,3- dimethylmorpholine-4-carbonyl)-7-methoxy-1,4- dihydrochromeno[4,3- c]pyrazol-8-yl)nicotinonitrile Compound 28

  (1-(3-chloro-5-

m/z: 552 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.59 (s, 1H), 7.43-7.42 (m,1H), 7.30 (d, J = 2.1 Hz, 1H), 7.23 (dd, J = 8.5, 1.7 Hz, 2H), 6.66 (s,1H), 6.55 (d, J = 2.4 Hz, 1H), 5.46 (s, 2H), 4.06 (t, J = 4.8 Hz, 2H),3.88 (s, 3H), 3.86-3.84 (m, 5H), 3.49 (s, 2H), 1.53 (s, 6H).fluorophenyl)-7-methoxy- 8-(1-methyl-1H-pyrazol- 3-yl)-1,4-dihydrochromeno[4,3- c]pyrazol-3-yl)(3,3- dimethylmorpholino) methanoneCompound 29

m/z: 520 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.58 (s, 1H), 7.42 (s, 1H),7.29-7.28 (m, 3H), 6.64 (s, 1H), 6.51 (d, J = 2.0 Hz, 1H), 5.47 (s, 2H),3.87 (s, 3H), 3.85 (s, 3H), 3.27 (s, 3H), 2.42 (s, 3H), 1.52 (s, 9H).N-tert-butyl-1-(3-chloro- 5-methylphenyl)-7- methoxy-N-methyl-8-(1-methyl-1H-pyrazol-3-yl)- 1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 30

  (1-(3-chloro-5-

m/z: 548 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.55 (s, 1H), 7.40 (s, 1H),7.30-7.27 (m, 3H), 6.65 (s, 1H), 6.51 (d, J = 2.1 Hz, 1H), 5.47 (s, 2H),4.08 (t, J = 4.8 Hz, 2H), 3.87 (s, 3H),3.85-3.84 (m, 5H), 3.49 (s, 2H),2.42 (s, 3H), 1.53 (s, 6H). methylphenyl)-7- methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1,4- dihydrochromeno[4,3- c]pyrazol-3-yl)(3,3-dimethylmorpholino) methanone Compound 31

m/z: 536 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 7.68 (s, 1H), 7.31 (d, J =2.0 Hz, 1H), 7.23 (t, J = 2.0 Hz, 1H), 7.03-7.00 (m, 2H), 6.67 (s, 1H),6.54 (d, J = 2.0 Hz, 1H), 5.49 (s, 2H), 3.90 (s, 3H),3.88 (s, 3H), 3.84(s, 3H), 3.29 (s, 3H), 1.54 (s, 9H). N-tert-butyl-1-(3-chloro-5-methoxyphenyl)-7- methoxy-N-methyl-8-(1- methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide Compound 32

  (1-(3-chloro-5-

m/z: 564 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.64 (s, 1H), 7.30 (d, J =2.1 Hz, 1H), 7.19-7.18 (m, 1H), 7.04- 7.03 (m, 1H), 6.99-6.98 (m, 1H),6.65 (s, 1H), 6.52 (d, J = 2.2 Hz, 1H), 5.47 (s, 2H), 4.09-4.07 (m, 2H),3.88 (s, 3H), 3.85 (s, 5H), 3.81 (s, 3H), 3.49 (s, 2H), 1.53 (s, 6H).methoxyphenyl)-7- methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1,4-dihydrochromeno[4,3- c]pyrazol-3-yl)(3,3- dimethylmorpholino) methanoneCompound 33

  5-(1-(3-chloro-5-

m/z: 586 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.74 (t, J = 1.6 Hz, 2H),7.91 (t, J = 2.0 Hz, 1H), 7.15 (t, J = 2.0 Hz, 1H), 7.07 (t, J = 2.0 Hz,1H), 7.01 (t, J = 2.0 Hz, 1H), 6.88 (s, 1H), 6.72 (s, 1H), 5.52 (s, 2H),4.09 (t, J = 2.0 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 1H), 3.84 (s, 4H), 3.49(s, 2H), 1.53 (s, 6H). methoxyphenyl)-3-(3,3- dimethylmorpholine-4-carbonyl)-7-methoxy-1,4- dihydrochromeno[4,3- c]pyrazol-8-yl)nicotinonitrile Compound 34

m/z: 558 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.68-8.66 (m, 2H), 7.85-7.84(m, 1H), 7.10 (t, J = 1.6 Hz, 1H), 7.00-6.95 (m, 2H), 6.83 (s, 1H), 6.65(s, 1H), 5.45 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.21 (s, 3H), 1.45(s, 9H). N-tert-butyl-1-(3-chloro- 5-methoxyphenyl)-8-(5-cyanopyridin-3-yl)-7- methoxy-N-methyl-1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 35

m/z: 564 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃): 8.75-8.73 (m, 2H), 7.92 (t, J= 1.6 Hz, 1H), 7.17 (t, J = 1.6 Hz, 1H), 7.05 (t, J = 1.6 Hz, 1H), 7.02(t, J = 1.6 Hz, 1H), 6.90 (s, 1H), 6.70 (s, 1H), 5.54 (s, 2H), 3.30 (s,3H), 1.54 (s, 9H). N-tert-butyl-1-(3-chloro- 5-D₃-methoxyphenyl)-8-(5-cyanopyridin-3-yl)-7- D₃-methoxy-N-methyl- 1H,4H-chromeno[4,3-c]pyrazole-3-carboxamide Compound 36

m/z: 532 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ ppm 7.69 (s, 1H), 7.29 (d, J= 2 Hz, 1H), 6.73 (s, 2H), 6.64 (s, 1H), 6.57 (s, 1H), 6.48 (d, J = 2.4Hz, 1H), 5.48 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.80 (s, 6H), 3.28(s, 3H), 1.52 (s, 9H). N-tert-butyl-1-(3,5- dimethoxyphenyl)-7-methoxy-N-methyl-8-(1- methyl-1H-pyrazol-3-yl)- 1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 37

m/z: 517 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 8.19 (s, 1 H), 7.16-7.11 (m,2 H), 6.74- 6.71 (m, 3 H), 6.63-6.62 (m, 2 H), 6.12-6.10 (m, 1 H), 5.46(s, 1 H), 3.89 (s, 3 H), 3.79 (s, 6 H), 3.27 (s, 3 H), 1.52 (s, 9 H).N-tert-butyl-1-(3,5- dimethoxyphenyl)-7- methoxy-N-methyl-8-(1H-pyrrol-3-yl)-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamide Compound38

  (1-(3,5- dimethoxyphenyl)-7-

m/z: 592 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.72 (s, 1H), 7.30 (d, J =2.0 Hz, 1H), 6.71 (d, J = 2.4 Hz, 2H), 6.65 (s, 1H), 6.59 (t, J = 2.4Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 5.48 (s, 2H), 4.59-4.53 (m, 1H),4.40- 4.32 (m, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.81 (s, 6H), 3.65-3.58(m, 1H), 3.10 (q, J = 13.6 Hz, 2H), 2.84-2.79 (m, 1H), 1.58 (s, 6H).methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1,4- dihydrochromeno[4,3-c]pyrazol-3-yl)-(S-oxo- 3,3- dimethylthiomorpholino) methanone Compound39

  (1-(3,5-

m/z: 607 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J = 5.2 Hz, 1H),7.64-77.60 (m, 1H), 7.17-7.13 (m, 1H), 6.86 (s, 1H), 6.69 (s, 1H), 6.63(d, J = 2.4 Hz, 2H), 6.55 (t, J = 2.0 Hz, 1H), 5.51 (s, 2H), 4.58-4.52(m, 1H), 4.40-4.33 (m, 1H), 3.80 (s, 9H), 3.63- 3.56 (m, 1H), 3.10 (q, J= 13.6 Hz, 2H), 2.84-2.78 (m, 1H), 1.58 (s, 6H). dimethoxyphenyl)-8-(2-fluoropyridin-3-yl)-7- methoxy-1,4- dihydrochromeno[4,3-c]pyrazol-3-yl)(S-oxo-3,3- dimethylthiomorpholino) methanone Compound 40

  (1-(3,5-

m/z: 589 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.53 (m, 1H), 7.66 (m, 2H),7.13 (m, 1H), 6.70-6.68 (m, 2H), 6.62-6.20 (m, 2H), 5.51 (s, 2H), 4.53(m, 1H), 4.37 (m, 1H), 3.86 (s, 2H), 3.80 (s, 6H), 3.77 (s, 1H), 3.57(m, 1H), 3.11- 3.08 (m, 2H), 2.82 (m, 1H), 1.79 (s, 3H), 1.69 (s, 3H).dimethoxyphenyl)-7- methoxy-8-(pyridin-2-yl)- 1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(S-oxo-3,3- dimethylthiomorpholino) methanone Compound 41

  (1-(3,5-

m/z: 575 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 8.13 (d, J = 4.0 Hz, 1H),7.63-7.59 (m, 1H), 7.16 (t, J = 5.2 Hz, 1H), 6.82 (s, 2H), 6.68 (s, 1H),6.62 (d, J = 2.0 Hz, 2H), 6.53 (s, 1H), 5.51 (s, 2H), 4.10 (t, J = 1.6Hz, 2H), 3.84 (t, J = 4.8 Hz, 2H), 3.80 (s, 9H), 3.50 (s, 2H), 1.55 (s,6H). dimethoxyphenyl)-8-(2- fluoropyridin-3-yl)-7- methoxy-1,4-dihydrochromeno[4,3- c]pyrazol-3-yl)(3,3- dimethylmorpholino) methanoneCompound 42

  (1-(3,5-

m/z: 571 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 8.35-8.30 (m, 2H), 7.37 (s,1H), 6.86 (s, 1H), 6.7 (s, 1H), 6.68 (d, J = 2.0 Hz, 2H), 6.60 (t, J =2.0 Hz, 1H), 5.51 (s, 2H), 4.12 (t, J = 4.8 Hz, 2H), 3.86 (t, J = 5.2Hz, 2H), 3.80 (s, 9H), 3.5 (s, 2H), 2.34 (s, 3H), 1.55 (s, 6H).dimethoxyphenyl)-7- methoxy-8-(5- methylpyridin-3-yl)-1,4-dihydrochromeno[4,3- c]pyrazol-3-yl)(3,3- dimethylmorpholino) methanoneCompound 43

m/z: 582 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.73-8.71 (m, 2H), 7.85-7.84(m, 1H), 6.87 (s, 1H), 6.69-6.62 (m, 4H), 5.54 (s, 2H), 4.12 4.10 (m,2H), 3.86- 3.84 (m, 8H), ), 3.84 (s, 3H), 3.49 (s, 2H), 1.53 (s, 6H).5-(1-(3,5- dimethoxyphenyl)-3-(3,3- dimethylmorpholine-4-carbonyl)-7-methoxy-1,4- dihydrochromeno[4,3- c]pyrazol-8-yl)nicotinonitrile Compound 44

  (1-(3,5-

m/z: 603 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 8.37-8.32 (m, 2H), 7.39 (s,1H), 6.90 (s, 1H), 6.70-6.68 (m, 3H), 6.60-6.59 (m, 1H), 5.53 (s, 2H),4.60-4.54 (m, 1H), 4.41-4.35 (m, 1H), 3.80 (s, 9H), 3.65-3.58 (m, 1H),3.16-3.06 (m, 2H), 2.85-2.81 (m, 1H), 2.32 (s, 3H) 1.78 (s, 6H).dimethoxyphenyl)-7- methoxy-8-(5- methylpyridin-3-yl)-1,4-dihydrochromeno[4,3- c]pyrazol-3-yl)(S-oxo-3,3- dimethylthiomorpholino)methanone Compound 45

m/z: 529 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.52-8.51 (m, 1H), 7.67-7.58(m, 3H), 7.12-7.09 (m, 1H), 6.71 (d, J = 2.3 Hz, 2H), 6.67 (s, 1H), 6.53(t, J = 2.2 Hz, 1H), 5.52 (s, 2H), 3.85 (s, 3H), 3.80 (s, 6H), 3.28 (s,3H), 1.52 (s, 9H). N-tert-butyl-1-(3,5- dimethoxyphenyl)-7-methoxy-N-methyl-8- (pyridin-2-yl)-1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 46

m/z: 557 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1 H), 7.95-7.90 (m,1 H), 7.53- 7.44 (m, 2 H), 7.21 (s, 1 H), 6.70-6.66 (m, 3 H), 6.55 (s, 1H), 5.57 (s, 2 H), 3.86-3.79 (m, 12 H), 3.49 (s, 3 H), 1.54 (s, 6 H).(1-(3,5- dimethoxyphenyl)-7- methoxy-8-(pyridin-2-yl)-1,4-dihydrochromeno[4,3- c]pyrazol-3-yl)(3,3- dimethylmorpholino)methanone Compound 47

m/z: 508 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ = 7.57 (s, 1 H), 7.30 (d, J= 2.0 Hz, 1 H), 7.18-7.15 (m, 2 H), 6.97- 6.92 (m, 1 H), 6.66 (s, 1 H),6.53 (d, J = 2.4 Hz, 1 H), 5.46 (s, 2 H), 3.88 (s, 3 H), 3.85 (s, 3 H),3.26 (s, 3 H), 1.52 (s, 9 H). N-tert-butyl-1-(3,5- difluorophenyl)-7-methoxy-N-methyl-8-(1- methyl-1H-pyrazol-3-yl)- 1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 48

  5-[1-(3,5-difluorophenyl)- 3-(S-oxo-3,3- dimethylthiomorpholino)-7-methoxy-1H,4H-

m/z: 590 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.76 (d, J = 1.6 Hz, 1H),8.66 (d, J = 2.2 Hz, 1H), 7.96 (t, J = 2.1 Hz, 1H), 7.15-7.11 (m, 2H),7.05-7.00 (m, 1H), 6.87 (s, 1H), 6.75 (s, 1H), 5.51 (s, 2H), 4.57-4.44(m, 1H), 4.44-4.27 (m, 1H), 3.86 (s, 3H), 3.56- 3.53 (m, 1H), 3.10 (q, J= 13.7 Hz, 2H), 2.85-2.81 (m, 1H), 1.80 (s, 3H), 1.69 (s, 3H).chromeno[4,3-c]pyrazol- 8-yl]pyridine-3- carbonitrile Compound 49

  5-(1-(3,5-difluorophenyl)- 3-(4-hydroxy-2,2- dimethylpiperidine-1-carbonyl)-7-methoxy-1,4- dihydrochromeno[4,3-

m/z: 572 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.75 (d, J = 2.0 Hz, 1H),8.66 (d, J = 2.2 Hz, 1H), 7.96 (t, J = 2.1 Hz, 1H), 7.18-7.12 (m, 2H),7.01-6.96 (m, 1H), 6.89 (s, 1H), 6.74 (s, 1H), 5.55-5.43 (m, 2H), 4.24-4.17 (m, 1H), 4.09 (m, 1H), 3.85 (s, 3H), 3.84 (m, 1H), 3.69-3.62 (m,1H), 2.19-2.13 (m, 1H), 1.92-1.88 (m, 1H), 1.79- 1.70 (m, 1H), 1.60 (s,6H). c]pyrazol-8- yl)nicotinonitrile Compound 50

m/z: 536 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃) δ 7.59 (s, 1H), 7.30 (d, J =2.0 Hz, 1H), 7.19-7.10 (m, 2H), 7.01- 6.93 (m, 1H), 6.66 (s, 1H), 6.55(d, J = 2.0 Hz, 1H), 5.46 (s, 2H), 4.10- 4.03 (m, 2H), 3.89-3.78 (m,8H), 3.49 (s, 2H), 1.53 (s, 6H). (1-(3,5-difluorophenyl)-7-methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1,4- dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3- dimethylmorpholino) methanone Compound 51

  N-tert-butyl-1-(3-fluoro-5-

m/z: 520 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.66 (s, 1H), 7.30 (d, J =2.2 Hz, 1H), 6.96-6.89 (m, 2H), 6.74 (dt, J = 10.3, 2.3 Hz, 1H), 6.65(s, 1H), 6.52 (d, J = 2.2 Hz, 1H), 5.47 (s, 2H), 3.87 (s, 3H), 3.84 (s,3H), 3.81 (s, 3H), 3.27 (s, 3H), 1.52 (s, 9H). methoxyphenyl)-7-methoxy-N-methyl-8-(1- methyl-1H-pyrazol-3-yl)- 1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 52

  (3,3-

m/z: 548 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.64 (s, 1H), 7.30 (d, J =2.2 Hz, 1H), 6.95-6.87 (m, 2H), 6.75 (d, J = 10.3 Hz, 1H), 6.65 (s, 1H),6.52 (d, J = 2.2 Hz, 1H), 5.47 (s, 2H), 4.13-4.04 (m, 2H), 3.91- 3.76(m, 10H), 3.49 (s, 2H), 2.01 (s, 1H), 1.53 (s, 6H).dimethylmorpholino)(1- (3-fluoro-5- methoxyphenyl)-7-methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1,4- dihydrochromeno[4,3-c]pyrazol-3-yl)methanone Compound 53

m/z: 542 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.72 (dd, J = 7.4, 2.0 Hz,2H), 7.90 (t, J = 2.1 Hz, 1H), 6.95-6.86 (m, 3H), 6.79 (d, J = 10.4 Hz,1H), 6.71 (s, 1H), 5.53 (s, 2H), 3.86 (d, J = 14.5 Hz, 6H), 3.28 (s,3H), 1.52 (d, J = 4.2 Hz, 9H). N-tert-butyl-8-(5-cyanopyridin-3-yl)-1-(3- fluoro-5-methoxyphenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 54

m/z: 493 [M + H]⁺ N-tert-butyl-8-(2- fluoropyridin-3-yl)-7-methoxy-N-methyl-1- (thiophen-3-yl)-1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 55

  (1-(thiophen-3-yl)-7- methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1,4-

m/z: 538 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 7.56 (m, 2H), 7.51 (m, 1H),7.32 (s, 1H), 7.27 (t, 1H), 6.67 (s, 1H), 6.54 (d, 2H), 5.32 (s, 2H),4.58 (m, 1H), 4.40 (m, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.6 (m, 1H),3.05 (m, 2H), 2.85 (m, 1H), 1.80 (s, 3H), 1.60 (s, 3H).dihydrochromeno[4,3- c]pyrazol-3-yl)(S-oxo-3,3- dimethylthiomorpholino)methanone Compound 56

  (4-hydroxy-2,2- dimethylpiperidin-1-yl)(7- methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen- 3-yl)-1,4- dihydrochromeno[4,3-

m/z: 520 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 7.534 (s, 1H), 7.457 (m, 1H),7.363 (s, 1H), 7.326-7.320 (d, 1H), 7.245 (s, 1H), 6.445-6.440 (s, 1H),5.517-5.438 (m, 2H), 4.240-4.220 (m, 1H), 4.118-4.07 (t, 1H, J = 9.6Hz), 3.915 (s, 3H), 3.883 (s, 3H), 3.655-3.606 (m, 2H), 2.132 (s, 1H),2.050 (s, 1H), 1.886-1.756 (m, 2H), 1.704 (s, 3H), 1.525 (s, 3H).c]pyrazol-3-yl)methanone Compound 57

m/z: 475 [M + H]⁺ N-tert-butyl-7-methoxy- N-methyl-8-(pyridin-2-yl)-1-(thiophen-3-yl)-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 58

  N-tert-butyl-7-methoxy- N-methyl-8-(5-

m/z: 489 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 2H), 7.52 (dd, J =3.2, 1.3 Hz, 1H), 7.48 (d, J = 5.1 Hz, 1H), 7.43 (s, 1H), 7.23 (dd, J =5.1, 1.3 Hz, 1H), 6.76 (s, 1H), 6.67 (s, 1H), 5.52 (s, 2H), 3.81 (s,3H), 3.27 (s, 3H), 2.33 (s, 3H), 1.52 (s, 9H). methylpyridin-3-yl)-1-(thiophen-3-yl)-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 59

  N-tert-butyl-8-(2-

m/z: 509 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.33 (dd, J = 4.8, 1.9 Hz,1H), 7.52- 7.45 (m, 2H), 7.39 (dd, J = 5.1, 3.2 Hz, 1H), 7.24- 7.16 (m,2H), 6.71 (s, 1H), 6.68 (s, 1H), 5.52 (s, 2H), 3.76 (s, 3H), 3.26 (s,3H), 1.51 (s, 9H). chloropyridin-3-yl)-7- methoxy-N-methyl-1-(thiophen-3-yl)-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 60

  (3,3- dimethylmorpholino)(8- (2-fluoropyridin-3-yl)-7-

m/z: 521 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 8.133 (s, 1H), 7.667-7.632(m, 1H), 7.488-7.424 (m, 2H), 7.210-7.194 (m, 2H), 6.789-6.787 (d, 1H, J= 0.8 Hz), 6.684 (s, 1H), 5.517 (s, 2H), 4.104-4.078 (t, 2H),3.859-3.832 (t, 2H), 3.794 (s, 3H), 3.483 (s, 2H), 1.529 (s, 6H).methoxy-1-(thiophen-3- yl)-1,4- dihydrochromeno[4,3-c]pyrazol-3-yl)methanone Compound 61

  N-tert-butyl-8-(2-fluoro-5- methylpyridin-3-yl)-7-

m/z: 507 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.49 (dd, J =3.2, 1.3 Hz, 1H), 7.43 (dd, J = 5.0, 3.3 Hz, 2H), 7.21 (dd, J = 5.1, 1.3Hz, 1H), 6.76 (d, J = 0.8 Hz, 1H), 6.67 (s, 1H), 5.51 (s, 2H), 3.79 (s,3H), 3.27 (s, 3H), 2.31 (s, 3H), 1.51 (s, 9H). methoxy-N-methyl-1-(thiophen-3-yl)-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 62

  N-tert-butyl-8-(2-

m/z: 492 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.49 (dd, J = 3.2, 1.3 Hz,1H), 7.40 (dd, J = 5.1, 3.2 Hz, 1H), 7.32- 7.27 (m, 1H), 7.21 (dd, J =5.1, 1.3 Hz, 1H), 7.19- 7.01 (m, 3H), 6.79 (s, 1H), 6.68 (s, 1H), 5.50(s, 2H), 3.78 (s, 3H), 3.26 (s, 3H), 1.51 (s, 9H).fluorophenyl)-7-methoxy- N-methyl-1-(thiophen-3- yl)-1,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide Compound 63

m/z: 574 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.78 (s, 1H),7.71 (s, 1H), 7.56 (s, 1H), 7.29 (d, J = 2.2 Hz, 1H), 6.67 (s, 1H), 6.56(d, J = 2.2 Hz, 1H), 5.45 (s, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 3.26 (s,3H), 1.53 (s, 9H). N-tert-butyl-1-(3-chloro- 5-(trifluoromethyl)phenyl)- 7-methoxy-N-methyl-8- (1-methyl-1H-pyrazol-3-yl)-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamide Compound 64

  methyl 2-amino-5-(3-(tert-

m/z: 578 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J = 2.4 Hz, 1H),8.02 (d, J = 2.4 Hz, 1H), 7.15 (dt, J = 17.7, 8.8 Hz, 2H), 6.97- 6.88(m, 1H), 6.80 (s, 1H), 6.70 (s, 1H), 5.46 (s, 2H), 3.91 (s, 3H), 3.82(s, 3H), 3.25 (d, J = 9.5 Hz, 3H), 1.52 (d, J = 3.6 Hz, 9H).butyl(methyl)carbamoyl)- 1-(3,5-difluorophenyl)-7- methoxy-1,4-dihydrochromeno[4,3- c]pyrazol-8-yl)nicotinate Compound 65

m/z: 616 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.99 (d, J = 2.2 Hz, 1H),8.73 (d, J = 2.0 Hz, 1H), 8.14 (s, 1H), 7.51 (s, 3H), 6.87 (s, 1H), 6.74(s, 1H), 5.50 (s, 2H), 3.84 (s, 3H), 3.27 (s, 3H), 1.52 (s, 9H).N-tert-butyl-1-(3,5- dichlorophenyl)-7- methoxy-N-methyl-8-(5-sulfamoylpyridin-3-yl)- 1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 66

m/z: 583 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): δ 7.79 (s, 1H), 7.58-7.57 (m,4H), 7.11 (s, 1H), 6.71 (s, 1H), 5.48 (s, 2H), 4.83 (s, 2H), 3.93 (s,3H), 3.28 (s, 3H), 1.54 (s, 9H). 8-(1-(2-amino-2-oxoethyl)-1H-pyrazol-4- yl)-N-tert-butyl-1-(3,5- dichlorophenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 67

m/z: 598 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J = 1.2 Hz, 1H),8.17 (d, J = 6.1 Hz, 1H), 7.70 (d, J = 3.9 Hz, 1H), 7.46 (t, J = 1.9 Hz,2H), 6.88 (s, 1H), 6.73 (s, 1H), 5.51 (d, J = 11.8 Hz, 2H), 3.82 (s,3H), 3.26 (s, 3H), 1.52 (s, 9H). N-tert-butyl-8-(2- carbamoyl-5-fluoropyridin-4-yl)-1-(3,5- dichlorophenyl)-7- methoxy-N-methyl-1,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide Compound 68

  2-(4-(1-(3-chloro-5-

m/z: 595 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.50 (s, 1H),7.43 (d, J = 0.9 Hz, 1H), 7.35-7.28 (m, 1H), 7.25 (d, J = 2.0 Hz, 1H),7.07 (s, 1H), 6.69 (s, 1H), 5.46 (s, 2H), 4.80 (s, 2H), 4.11-4.00 (m,2H), 3.91 (s, 3H), 3.89-3.80 (m, 2H), 3.50 (s, 2H), 1.53 (s, 6H).fluorophenyl)-3-(3,3- dimethylmorpholine-4- carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3- c]pyrazol-8-yl)-1H- pyrazol-1-yl)acetamide Compound69

m/z: 566 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J = 1.4 Hz, 1H),8.17 (d, J = 6.2 Hz, 1H), 7.12 (d, J = 4.8 Hz, 2H), 6.91 (s, 2H), 6.73(s, 1H), 5.51 (s, 2H), 3.82 (s, 3H), 3.26 (s, 3H), 1.52 (s, 9H).N-tert-butyl-8-(2- carbamoyl-5- fluoropyridin-4-yl)-1-(3,5-difluorophenyl)-7- methoxy-N-methyl-1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 70

  24-[1-(3,5- difluorophenyl)-3-(S-oxo-

m/z: 611 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.47 (s, 1H),7.17 (dd, J = 6.8, 2.1 Hz, 2H), 7.11- 7.01 (m, 2H), 6.69 (s, 1H), 6.20(s, 1H), 5.48 (s, 1H), 5.47 (s, 2H), 4.80 (s, 2H), 4.57-4.30 (m, 2H),3.91 (s, 3H), 3.56-3.50 (m, 1H), 3.10 (q, J = 13.8 Hz, 2H), 2.83-2.79(m, 1H), 1.60 (s, 6H). 3,3- dimethylthiomorpholino)- 7-methoxy-1H,4H-chromeno[4,3-c]pyrazol- 8-yl]-(1H-pyrazol-1- yl)acetamide Compound 71

  4-(1-(3,5-difluorophenyl)-

m/z: 594 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J = 1.6 Hz, 1H),8.17 (d, J = 6.2 Hz, 1H), 7.69 (d, J = 4.0 Hz, 1H), 7.13-7.03 (m, 2H),6.95-6.90 (m, 1H), 6.89 (d, J = 1.2 Hz, 1H), 6.74 (s, 1H), 5.60 (d, J =4.0 Hz, 1H), 5.53 (s, 2H), 4.13-4.02 (m, 2H), 3.87- 3.79 (m, 5H), 3.49(s, 2H), 1.53 (s, 6H). 3-(3,3- dimethylmorpholine-4-carbonyl)-7-methoxy-1,4- dihydrochromeno[4,3- c]pyrazol-8-yl)-5-fluoropicolinamide Compound 72

m/z: 591 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, 1H), 7.45 (s, 1H),7.08 (s, 1H), 6.90 (d, J = 10.1 Hz, 2H), 6.83 (d, J = 10.3 Hz, 1H), 6.67(s, 1H), 5.48 (s, 3H), 4.79 (s, 2H), 4.14-4.02 (m, 2H), 3.90 (s, 3H),3.88-3.78 (m, 4H), 3.49 (s, 2H), 1.53 (s, 6H). 2-(4-(3-(3,3-dimethylmorpholine-4- carbonyl)-1-(3-fluoro-5- methoxyphenyl)-7-methoxy-1,4- dihydrochromeno[4,3- c]pyrazol-8-yl)-1H-pyrazol-1-yl)acetamide Compound 73

  (3,3-

m/z: 578 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.70 (s, 1H), 7.37 (s, 1H),7.06 (s, 1H), 6.95-6.86 (m, 2H), 6.83 (d, J = 10.3 Hz, 1H), 6.65 (s,1H), 5.47 (s, 2H), 4.27- 4.17 (m, 2H), 4.14- 4.03 (m, 2H), 4.00 (d, J =4.4 Hz, 2H), 3.89 (s, 3H), 3.86 (d, J = 5.4 Hz, 2H), 3.83 (s, 3H), 3.49(s, 2H), 1.53 (s, 6H). dimethylmorpholino)(1- (3-fluoro-5-methoxyphenyl)-8-(1-(2- hydroxyethyl)-1H- pyrazol-4-yl)-7-methoxy-1,4-dihydrochromeno[4,3- c]pyrazol-3-yl)methanone Compound 74

m/z: 553 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J = 1.6 Hz, 1H),7.13 (dd, J = 8.6, 3.9 Hz, 3H), 6.91 (d, J = 18.1 Hz, 2H), 6.72 (s, 1H),5.50 (s, 2H), 4.72 (d, J = 5.1 Hz, 2H), 3.82 (s, 3H), 3.26 (s, 3H), 1.52(s, 9H). N-tert-butyl-1-(3,5- difluorophenyl)-8-(5- fluoro-2-(hydroxymethyl)pyridin- 4-yl)-7-methoxy-N- methyl-1,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide Compound 75

  N-tert-butyl-8-(1-(2-

m/z: 508 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.72 (s, 1H), 7.58-7.50 (m,2H), 7.41 (s, 1H), 7.25 (s, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.63 (s, 1H),5.49 (s, 2H), 4.32- 4.18 (m, 2H), 4.01 (d, J = 4.2 Hz, 2H), 3.89 (s,3H), 3.27 (s, 3H), 1.51 (s, 9H). hydroxyethyl)-1H-pyrazol-4-yl)-7-methoxy- N-methyl-1-(thiophen-3- yl)-1,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide Compound 76

m/z: 570 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 7.70 (s, 1H), 7.54 (s, 3H),7.47 (s, 1H), 7.07 (s, 1H), 6.67 (s, 1H), 5.44 (s, 2H), 4.24 (t, J = 4.8Hz, 2H), 4.02-4.01 (m, 2H), 3.90 (s, 3H), 3.26 (s, 3H), 1.52 (s, 9H).N-tert-butyl-1-(3,5- dichlorophenyl)-8-(1-(2- hydroxyethyl)-1H-pyrazol-4-yl)-7-methoxy- N-methyl-1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 77

  (1-(3-chloro-5-

m/z: 582 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.70 (s, 1H), 7.43 (s, 2H),7.35-7.28 (m, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.05 (s, 1H), 6.68 (s, 1H),5.45 (s, 2H), 4.32-4.15 (m, 2H), 4.05 (dd, J = 13.3, 8.0 Hz, 4H), 3.90(s, 3H), 3.88-3.79 (m, 2H), 3.49 (s, 2H), 1.53 (s, 6H).fluorophenyl)-8-(1-(2- hydroxyethyl)-1H- pyrazol-4-yl)-7-methoxy-1,4-dihydrochromeno[4,3- c]pyrazol-3-yl)(3,3- dimethylmorpholino)methanone Compound 78

m/z: 566 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.69 (s, 1H), 7.42 (s, 1H),7.19 (s, 1H), 7.08 (d, J = 2.7 Hz, 2H), 7.01 (s, 1H), 6.65 (s, 1H), 5.46(s, 2H), 4.28-4.18 (m, 2H), 4.01 (d, J = 4.4 Hz, 2H), 3.89 (s, 3H), 3.84(s, 3H), 3.27 (s, 3H), 1.50 (d, J = 17.8 Hz, 9H).N-tert-butyl-1-(3-chloro- 5-methoxyphenyl)-8-(1- (2-hydroxyethyl)-1H-pyrazol-4-yl)-7-methoxy- N-methyl-1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 79

m/z: 584 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J = 1.8 Hz, 2H),7.42 (t, J = 1.8 Hz, 1H), 7.35-7.29 (m, 1H), 7.19 (dd, J = 6.9, 2.1 Hz,1H), 7.10-7.02 (m, 1H), 6.84 (s, 1H), 6.71 (s, 1H), 5.45 (s, 2H), 4.67(s, 2H), 3.80 (s, 3H), 3.25 (s, 3H), 1.53 (s, 9H). N-tert-butyl-1-(3,5-dichlorophenyl)-8-(3- fluoro-5- (hydroxymethyl)phenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 80

m/z: 584 [M + H]⁺ ¹H NMR (400 MHz, DMSO) δ 7.97-7.96 (m, 1H), 7.86 (d, J= 1.6 Hz, 2H), 7.75 (s, 1H), 7.09 (s, 1H), 6.99 (s, 1H), 6.79 (s, 1H),5.35 (s, 2H), 4.31 (s, 2H), 3.86 (s, 3H), 3.17 (s, 3H), 1.44 (s, 9H).2-(4-(3-(tert- butyl(methyl)carbamoyl)- 1-(3,5-dichlorophenyl)-7-methoxy-1,4- dihydrochromeno[4,3- c]pyrazol-8-yl)-1H-pyrazol-1-yl)acetic acid Compound 81

m/z: 598 [M + H]⁺ ¹H NMR (400 MHz, MeOD) δ 7.98-.795 (m, 1H), 7.86 (dd,J = 7.2, 2.2 Hz, 1H), 7.60 (s, 3H), 7.14 (t, J = 9.1 Hz, 1H), 6.80 (d, J= 13.0 Hz, 2H), 5.38 (s, 2H), 3.81 (s, 3H), 3.23 (s, 3H), 1.54 (s, 9H).3-(3-(tert- butyl(methyl)carbamoyl)- 1-(3,5-dichlorophenyl)-7-methoxy-1,4- dihydrochromeno[4,3- c]pyrazol-8-yl)-4- fluorobenzoic acidCompound 82

m/z: 598 [M + H]⁺ ¹H NMR (400 MHz, MeOD) δ 7.71-7.69 (m, 4H), 7.57-7.54(m, 1H), 7.29-7.26 (m, 1H), 6.86 (d, J = 8.4 Hz, 2H), 5.39 (s, 2H), 3.85(s, 3H), 3.22 (s, 3H), 1.51 (s, 9H). 3-(3-(tert-butyl(methyl)carbamoyl)- 1-(3,5-dichlorophenyl)-7- methoxy-1,4-dihydrochromeno[4,3- c]pyrazol-8-yl)-5- fluorobenzoic acid Compound 83

m/z: 596 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.75 (s, 1H), 7.49-7.42 (m,2H), 7.29- 7.24 (m, 2H), 7.06 (s, 1H), 6.67 (s, 1H), 5.45 (s, 2H), 4.95(s, 2H), 4.06 (m, 2H), 3.89-3.86 (m, 5H), 3.50 (s, 2H), 1.53 (s, 6H).2-(4-(1-(3-chloro-5- fluorophenyl)-3-(3,3- dimethylmorpholine-4-carbonyl)-7-methoxy-1,4- dihydrochromeno[4,3- c]pyrazol-8-yl)-1H-pyrazol-1-yl)acetic acid Compound 84

m/z: 580 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.46 (s, 1H),7.17 (s, 1H), 7.08-7.04 (m, 2H), 7.00 (s, 1H), 6.63 (s, 1H), 5.45 (s,2H), 4.95 (s, 2H), 3.86 (s, 3H), 3.77 (s, 3H), 3.25 (s, 3H), 1.2 (s,9H). 2-(4-(3-(tert- butyl(methyl)carbamoyl)- 1-(3-chloro-5-methoxyphenyl)-7- methoxy-1,4- dihydrochromeno[4,3- c]pyrazol-8-yl)-1H-pyrazol-1-yl)acetic acid Compound 85

m/z: 608 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.75 (s, 1H), 7.49 (s, 1H),7.17-7.00 (m, 4H), 6.66 (s, 1H), 5.47 (s, 2H), 4.95 (s, 2H), 4.07 (m,2H), 3.95-3.74 (m, 8H), 3.49 (s, 2H), 1.53 (s, 6H) 2-(4-(1-(3-chloro-5-methoxyphenyl)-3-(3,3- dimethylmorpholine-4- carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3- c]pyrazol-8-yl)-1H- pyrazol-1-yl)acetic acidCompound 86

m/z: 552 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.69 (s, 1H), 7.39 (s, 1H),7.14-7.13 (m, 2H), 7.03-6.96 (m, 2H), 6.62-6.60 (m, 1H), 5.43 (s, 2H),4.87 (s, 2H), 3.84 (s, 3H), 3.25 (s, 3H), 1.52 (s, 9H). 2-(4-(3-(tert-butyl(methyl)carbamoyl)- 1-(3,5-difluorophenyl)-7- methoxy-1,4-dihydrochromeno[4,3- c]pyrazol-8-yl)-1H- pyrazol-1-yl)acetic acidCompound 87

m/z: 580 [M + H]⁺ ¹H NMR (400 MHz, DMSO) δ 7.81 (s, 1H), 7.68-7.53 (m,3H), 7.12 (s, 1H), 6.94 (s, 1H), 6.80 (s, 1H), 5.37 (s, 2H), 4.62 (s,2H), 3.96-3.90 (m, 2H), 3.86 (s, 3H), 3.76- 3.70 (m, 2H), 3.42 (s, 2H),1.42 (s, 6H). 2-(4-(1-(3,5- difluorophenyl)-3-(3,3-dimethylmorpholine-4- carbonyl)-7-methoxy-1,4- dihydrochromeno[4,3-c]pyrazol-8-yl)-1H- pyrazol-1-yl)acetic acid Compound 88

m/z: 592 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.54 (s, 1H), 7.23 (s, 1H),6.89-6.73 (m, 4H), 6.48 (s, 1H), 5.40 (s, 2H), 4.73 (s, 2H), 4.06 (s,2H), 3.84 (s, 2H), 3.71 (s, 6H), 3.49 (s, 3H), 1.53 (s, 6H).2-(4-(3-(3,3- dimethylmorpholine-4- carbonyl)-1-(3-fluoro-5-methoxyphenyl)-7- methoxy-1,4- dihydrochromeno[4,3- c]pyrazol-8-yl)-1H-pyrazol-1-yl)acetic acid Compound 89

m/z: 611 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.53 (s, 3H),7.44 (s, 1H), 7.09 (s, 1H), 6.66 (s, 1H), 5.44 (s, 2H), 4.97 (s, 2H),3.88 (s, 3H), 3.26 (s, 3H), 3.08 (s, 3H), 2.99 (s, 3H), 1.52 (s, 9H).N-tert-butyl-1-(3,5- dichlorophenyl)-8-(1-(2- (dimethylamino)-2-oxoethyl)-1H-pyrazol-4- yl)-7-methoxy-N-methyl- 1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 90

m/z: 597 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.74 (s, 1H), 7.53 (d, J =10.4 Hz, 3H), 7.09 (s, 1H), 6.69 (s, 1H), 6.21 (s, 1H), 5.45 (s, 2H),4.80 (s, 2H), 3.91 (s, 3H), 3.26 (s, 3H), 2.79 (d, J = 4.9 Hz, 3H), 1.52(s, 9H). N-tert-butyl-1-(3,5- dichlorophenyl)-7- methoxy-N-methyl-8-(1-(2-(methylamino)-2- oxoethyl)-1H-pyrazol-4- yl)-1,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide Compound 91

m/z: 639 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.53 (dd, J =10.4, 1.8 Hz, 3H), 7.43 (s, 1H), 7.07 (s, 1H), 6.66 (s, 1H), 5.44 (s,2H), 4.97 (s, 2H), 4.05 (s, 2H), 3.90-3.83 (m, 5H), 3.49 (s, 2H), 3.08(s, 3H), 2.99 (s, 3H), 1.53 (s, 6H). 2-(4-(1-(3,5-dichlorophenyl)-3-(3,3- dimethylmorpholine-4- carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3- c]pyrazol-8-yl)-1H- pyrazol-1-yl)-N,N-dimethylacetamide Compound 92

m/z: 597 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.86-7.76 (m, 1H), 7.62 (dd,J = 6.8, 2.3 Hz, 1H), 7.49 (d, J = 1.8 Hz, 2H), 7.42 (t, J = 1.8 Hz,1H), 7.15 (t, J = 8.9 Hz, 1H), 6.82 (s, 1H), 6.72 (s, 1H), 5.47 (s, 2H),3.80 (s, 3H), 3.26 (s, 3H), 1.50 (d, J = 17.4 Hz, 9H).N-tert-butyl-8-(5- carbamoyl-2- fluorophenyl)-1-(3,5- dichlorophenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 93

  5-(1-(3,5- dichlorophenyl)-3-(3,3-

m/z: 622 [M + H]⁺ ¹H NMR (400 MHz, CDCl3) δ 8.86 (d, J = 2.1 Hz, 1H),8.62 (d, J = 2.1 Hz, 1H), 8.03 (t, J = 2.1 Hz, 1H), 7.53-7.46 (m, 3H),6.86 (s, 1H), 6.74 (s, 1H), 6.13 (d, J = 4.0 Hz, 1H), 5.48 (s, 2H),4.11- 4.02 (m, 2H), 3.89-3.80 (m, 5H), 3.50 (s, 2H), 3.06 (d, J = 4.8Hz, 3H), 1.53 (s, 6H). dimethylmorpholine-4- carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3- c]pyrazol-8-yl)-N- methylnicotinamide Compound 94

m/z: 623 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.53 (s, 3H),7.43 (s, 1H), 7.08 (s, 1H), 6.67 (s, 1H), 5.44 (s, 2H), 4.75 (s, 2H),4.08 (t, J = 7.8 Hz, 2H), 3.99 (t, J = 7.7 Hz, 2H), 3.89 (s, 3H), 3.26(s, 3H), 2.31-2.19 (m, 2H), 1.52 (s, 9H). 8-(1-(2-(azetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4- yl)-N-tert-butyl-1-(3,5- dichlorophenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 95

m/z: 638 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.82 (s, 1H), 8.66 (s, 1H),8.02 4, J = 2.1 Hz, 1H), 7.53-7.46 (m, 3H), 6.85 (s, 1H), 6.73 (s, 1H),5.48 (s, 2H), 4.09-4.02 (m, 2H), 3.93 (s, 3H), 3.88-3.81 (m, 5H), 3.50(s, 2H), 1.53 (s, 6H). 5-(1-(3,5-dichlorophenyl)- 3-(3,3-dimethylmorpholine-4- carbonyl)-7-methoxy-1,4- dihydrochromeno[4,3-c]pyrazol-8-yl)-N- methoxynicotinamide Compound 96

m/z: 597 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 1.8 Hz, 2H),7.50-7.42 (m, 3H), 7.26-7.21 (m, 1H), 6.86 (s, 1H), 6.72 (s, 1H), 5.48(s, 2H), 3.83 (s, 3H), 3.26 (s, 3H), 1.52 (s, 9H). N-tert-butyl-8-(3-carbamoyl-5- fluorophenyl)-1-(3,5- dichlorophenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 97

m/z: 579 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃) δ 7.73 (d, J = 7.5 Hz, 1H),7.54-7.45 (m, 3H), 7.39-7.35 (m, 2H), 7.16 (d, J = 7.5 Hz, 1H), 6.90 (s,1H), 6.65 (s, 1H), 5.49 (d, J = 28.7 Hz, 2H), 3.76 (s, 3H), 3.25 (s,3H), 1.50 (s, 9H). N-tert-butyl-8-(2- carbamoylphenyl)-1-(3,5-dichlorophenyl)-7- methoxy-N-methyl-1,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 98

m/z: 579 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.47 (s, 1H),7.21-7.11 (m, 2H), 7.08-6.96 (m, 2H), 6.69 (s, 1H), 6.21 (s, 1H), 5.52(s, 1H), 5.46 (s, 2H), 4.80 (s, 2H), 4.12- 3.99 (m, 2H), 3.91 (s, 3H),3.89-3.80 (m, 2H), 3.50 (s, 2H), 1.53 (s, 6H). 2-(4-(1-(3,5-difluorophenyl)-3-(3,3- dimethylmorpholine-4- carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3- c]pyrazol-8-yl)-1H- pyrazol-1-yl)acetamide Compound99

  8-(6-amino-5-

m/z: 577 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃) δ 8.12 (d, J = 2.0 Hz, 1H),7.49 (d, J = 1.9 Hz, 1H), 7.23-7.14 (m, 2H), 6.93 (t, J = 8.7 Hz, 1H),6.81 (s, 1H), 6.70 (s, 1H), 6.38 (s, 2H), 6.03 (s, 1H), 5.45 (s, 2H),3.82 (s, 3H), 3.26 (s, 3H), 3.00 (d, J = 4.8 Hz, 3H), 1.52 (s, 9H).(methylcarbamoyl)pyridin- 3-yl)-N-tert-butyl-1-(3,5- difluorophenyl)-7-methoxy-N-methyl-1,4- dihydrochromeno[4,3- c]pyrazole-3-carboxamideCompound 100

m/z: 636 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃) δ 8.57 (d, J = 1.8 Hz, 2H),7.74 (t, J = 2.1 Hz, 1H), 7.50-7.47 (m, 3H), 6.88 (s, 1H), 6.73 (s, 1H),5.49 (s, 2H), 4.09- 4.04 (m, 2H), 3.88-3.84 (m, 2H), 3.83 (s, 3H), 3.50(s, 2H), 3.15 (s, 3H), 3.00 (s, 3H), 1.53 (s, 6H).5-(1-(3,5-dichlorophenyl)- 3-(3,3- dimethylmorpholine-4-carbonyl)-7-methoxy-1,4- dihydrochromeno[4,3- c]pyrazol-8-yl)-N,N-dimethylnicotinamide Compound 101

Example 3:(1-(3,5-dichlorophenyl)-7-methoxy-8-(pyridin-2-yl)-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(4-hydroxy-2,2-dimethylpiperidin-1-yl)methanone(Compound 102)

Step 1: Synthesis of(8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(4-hydroxy-2,2-dimethylpiperidin-1-yl)methanone

To a solution of8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (500 mg, 1.07 mmol) in DMF (20 mL) was added2,2-dimethylpiperidin-4-ol (166 mg, 1.28 mmol), HATU (407 mg, 1.07 mmol)and diisopropyl ethyl amine (0.57 mL, 3.21 mmol) at RT under nitrogen.The reaction mixture was stirred at RT for 3 h. The reaction mixture wasquenched with sodium bicarbonate (10 mL, 10%), and extracted with EtOAc(2×50 mL). The combined organic layer was washed with brine (30 mL) anddried over anhydrous Na₂SO₄. The solvent was removed under vacuum; thecrude product was purified by column chromatography by using pet etherand ethyl acetate (5:1) as eluents to afford the desired compound (500mg, 80%) as a white solid.

Step 2: Synthesis of(1-(3,5-dichlorophenyl)-7-methoxy-8-(pyridin-2-yl)-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(4-hydroxy-2,2-dimethylpiperidin-1-yl)methanone(Compound 102)

To a solution of(8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(4-hydroxy-2,2-dimethylpiperidin-1-yl)methanone(200 mg, 0.35 mmol) in DMF (5 mL) was added 2-(tributylstannyl)pyridine(193 mg, 0.53 mmol) and Pd(dppf)Cl₂ (29 mg, 0.07 mmol) at RT undernitrogen. The reaction was microwaved at 120° C. for 2 hours. LCMSshowed the reaction was completed. The mixture was purified bypreparative HPLC to afford the desired compound (30 mg, 15%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ 8.98 (d, 1H), 8.07 (t, J=7.8 Hz, 1H),7.67 (d, J=7.8 Hz, 1H), 7.53 (d, J=1.8 Hz, 3H), 7.46 (t, J=1.8 Hz, 1H),7.22 (s, 1H), 6.74 (s, 1H), 5.54 (q, J=13.8 Hz, 2H), 4.23-4.04 (m, 2H),3.87 (s, 3H), 3.68-3.59 (m, 1H), 2.16 (s, 1H), 1.90 (dd, J=13.5, 4.9 Hz,1H), 1.75 (dd, J=24.2, 10.9 Hz, 1H), 1.68 (s, 3H), 1.53 (s, 3H).

Example 4.N-(1-amino-2-methyl-1-oxopropan-2-yl)-8-(5-carbamoylpyridin-3-yl)-1-(3,5-difluorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 104)

Step 1:8-bromo-N-(2-cyanopropan-2-yl)-1-(3,5-difluorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

A mixture of8-bromo-1-(3,5-difluorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (100 mg, 0.229 mmol), HATU 9104 mg, 0.275 mmol),2-amino-2-methylpropanenitrile (29 mg, 0.344 mmol) and DIPEA (89 mg,0.687 mmol0 in DMF (4 ml) was stirred at RT for 2 h. Then The mixturewas purified by Combi-Flash (mobile phase: acetonitrile/water (10 mMNH₄HCO₃) to afford8-bromo-N-(2-cyanopropan-2-yl)-1-(3,5-difluorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(95 mg, 82%). LCMS m/z [M+H]⁺ 503.0.

Step 2:8-bromo-N-(2-cyanopropan-2-yl)-1-(3,5-difluorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

At 0° C., to a solution of8-bromo-N-(2-cyanopropan-2-yl)-1-(3,5-difluorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(95 mg, 0.19 mmol) in DMF (4 mL), was added NaH (31 mg, 0.76 mmol) andCH₃I (54 mg, 0.38 mmol). The mixture was stirred at RT under N₂ for 2 h,quenched by sat, NH₄C₁, purified by Combi-Flash (mobile phase:acetonitrile/water (10 mM NH₄HCO₃) to afford8-bromo-N-(2-cyanopropan-2-yl)-1-(3,5-difluorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(70 mg, 71.4%) as white solid. LCMS m/z [M+H]⁺ 516.8.

Step 3:N-(2-cyanopropan-2-yl)-8-(5-cyanopyridin-3-yl)-1-(3,5-difluorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 105)

A mixture of8-bromo-N-(2-cyanopropan-2-yl)-1-(3,5-difluorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(70 mg, 0.136 mmol), 5-cyanopyridin-3-ylboronic acid (40 mg, 0.272mmol), P(tBu)₃PdG₂ (7 mg, 0.0136 mmol) and NaHCO₃ (34 mg, 0.408 mmol) inDMF (3 ml) and water (0.6 ml) was heated at 120° C. by Microwave for 1h. Then the mixture was purified by preparative HPLC to getN-(2-cyanopropan-2-yl)-8-(5-cyanopyridin-3-yl)-1-(3,5-difluorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(30 mg, 41%) as white solid. LCMS m/z [M+H]⁺ 541.0. ¹H NMR (400 MHz,CDCl₃): 8.75 (d, 1H, J=1.6 Hz), 8.65 (d, 1H, J=2.0 Hz), 7.96 (t, 1H,J=2.0 Hz), 7.17-7.14 (m, 2H), 7.04-6.99 (m, 1H), 6.86 (s, 1H), 6.75 (s,1H), 5.58 (s, 2H), 3.86 (s, 3H), 3.47 (s, 3H), 1.84 (s, 6H).

Step 4:N-(1-amino-2-methyl-1-oxopropan-2-yl)-8-(5-carbamoylpyridin-3-yl)-1-(3,5-difluorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 104)

A mixture ofN-(2-cyanopropan-2-yl)-8-(5-cyanopyridin-3-yl)-1-(3,5-difluorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(20 mg, 0.037 mmol), NH₄OH (0.5 ml) and H₂O₂ (0.5 ml) in MeOH (2 ml) wasstirred at 50° C. for 2 h. Then the mixture was purified by preparativeHPLC to getN-(1-amino-2-methyl-1-oxopropan-2-yl)-8-(5-carbamoylpyridin-3-yl)-1-(3,5-difluorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(12 mg, 56%) as white solid. LCMS m/z [M+H]⁺ 577.0. ¹H NMR (400 MHz,CDCl₃): 8.75 (d, 1H, J=1.6 Hz), 8.65 (d, 1H, J=2.0 Hz), 7.96 (t, 1H,J=2.0 Hz), 7.168-7.145 (m, 2H), 7.04-6.99 (m, 1H), 6.86 (s, 1H), 6.75(s, 1H), 5.58 (s, 2H), 3.86 (s, 3H), 3.47 (s, 3H), 1.84 (s, 6H).

The following compounds were prepared using procedures analogous tothose disclosed in Scheme 3.

Boronic Acid Amine Starting Starting Compound Material Material LC-MSNMR

m/z: 519 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃) δ 7.59 (s, 1H), 7.30 (d, J =2.0 Hz, 1H), 7.17 (dd, J = 6.7, 2.0 Hz, 2H), 6.97 (s, 1H), 6.67 (s, 1H),6.55 (d, J = 2.1 Hz, 1H), 5.52 (s, 2H), 3.86 (d, J = 22.6 Hz, 6H), 3.46(s, 3H), 1.83 (d, J = 7.1 Hz, 6H).N-(2-cyanopropan-2-yl)-1-(3,5-difluorophenyl)-7-methoxy-N-methyl-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 106

m/z: 560 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 9.158-9.153 (d, 1H, J = 2.0Hz), 8.764-8.758 (d, 1H, J = 2.4 Hz), 8.265- 8.260 (d, 1H, J = 2.0 Hz),7.163-7.146 (m, 2H), 7.034-6.981 (m, 1H), 6.877 (s, 1H), 6.748 (s, 1H),5.572 (s, 2H), 3.853 (s, 3H), 3.468 (s, 3H), 1.814 (s, 6H).5-(3-((2-cyanopropan-2-yl)(methyl)carbamoyl)-1-(3,5-difluorophenyl)-7-methoxy-1,4-dihydro-chromeno[4,3-c]pyrazole-8-yl)nicotinic acid Compound 107

m/z: 578 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 2H), 7.66 (s, 1H),7.52 (dd, J = 6.8, 1.8 Hz, 3H), 6.87 (s, 1H), 6.73 (s, 1H), 5.55 (s,2H), 4.76 (d, J = 5.5 Hz, 2H), 3.83 (s, 3H), 3.46 (s, 3H), 1.84 (s, 6H).N-(2-cyanopropan-2-yl)-1-(3,5-dichlorophenyl)-8-(5-(hydroxymethyl)pyridin-3-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 108

m/z: 577 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J = 1.6 Hz, 1H),8.17 (d, J = 6.2 Hz, 1H), 7.69 (d, J = 4.0, 1H), 7.12- 7.09 (m, 2H),6.99- 6.92 (m, 1H), 6.90 (d, J = 1.1 Hz, 1H), 6.74 (s, 1H), 5.56 (s,2H), 5.54 (d, J = 4.0 Hz, 1H), 3.83 (s, 3H), 3.45 (S, 3H), 1.84 (s, 6H).8-(2-carbamoyl-5-fluoropyridin-4-yl)-N-(2-cyanopropan-2-yl)-1-(3,5-difluorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 109

m/z: 575 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 8.92 (s, 1H), 8.68 (s, 1H),8.10 (s, 1H), 7.80 (m, 1H), 7.56 (m, 1H), 7.44 (s, 1H), 6.90 (s, 1H),6.76 (s, 1H), 5.58 (s, 2H), 3.90 (s, 3H), 3.48 (s, 3H), 1.49 (s, 6H).8-(5-carbamoylpyridin-3-yl)-1-(3-chloro-5-fluoro-phenyl)-N-(2-cyanopropan-2-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 110

Example 5.N-tert-butyl-8-(4-carbamoylpyrimidin-2-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 111)

Step 1:N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution of8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(100 mg, 0.19 mmol) in dioxane (3 mL) were added Pd(OAc)₂ (9 mg, 0.04mmol), PCy₃ (11 mg, 0.04 mmol) and KOAc (56 mg, 0.57 mmol). The mixturewas heated at 100° C. for 4 h. After cooling to r.t, the mixture wasconcentrated. The residue was purified by Combi-Flash (mobile phase:acetonitrile/water (10 mM NH₄HCO₃)) to affordN-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(30 mg, 27%) as a yellow solid.

Step 2:N-tert-butyl-8-(4-cyanopyrimidin-2-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution ofN-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(20 mg, 0.03 mmol) in dioxane (1.5 mL) and water (0.3 mL) was added2-chloropyrimidine-4-carbonitrile (10 mg, 0.06 mmol), Pd (dppf)Cl₂ (3mg, 0.003 mmol) and KF (3 mg, 0.06 mmol) at RT under nitrogen. Themixture was stirred at 90° C. for 2 h under MW conditions. Then themixture was directly purified by Combi-Flash (mobile phase:acetonitrile/water (10 mM NH₄HCO₃)) to affordN-tert-butyl-8-(4-cyanopyrimidin-2-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(12 mg, 75%) as a white solid. LCMS: m/z=563(M+H).

Step 3:N-tert-butyl-8-(4-carbamoylpyrimidin-2-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 111)

To a solution ofN-tert-butyl-8-(4-cyanopyrimidin-2-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamidein acetone/H₂O (2 mL/0.4 mL) was added NaOH (4 mg, 0.1 mmol) and H₂O₂(0.5 mL, 30%). The mixture was heated at 40° C. for 3 h. The solvent wasremoved and the crude was purified by Combi-Flash (mobile phase:acetonitrile/water (10 mM NH₄HCO₃)) to affordN-tert-butyl-8-(4-carbamoylpyrimidin-2-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(5 mg, 45%) as a white solid. LCMS m/z=581 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.98 (d, J=4.9 Hz, 1H), 7.92 (d, J=4.9 Hz, 1H), 7.71 (s, 1H),7.53-7.49 (m, 3H), 7.47 (t, J=1.8 Hz, 1H), 6.75 (s, 1H), 5.68 (s, 1H),5.53 (s, 2H), 3.90 (s, 3H), 3.27 (s, 3H), 1.52 (s, 9H).

The following compounds were prepared using procedures analogous tothose disclosed in Scheme 4.

Boronic Acid Amine Starting Starting Compound Material Material LC-MSNMR

m/z: 563 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.74 (d, J = 2.4 Hz, 1H),8.55 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 1.8 Hz, 2H), 7.42 (t, J = 1.8 Hz,1H), 7.17 (s, 1H), 6.74 (s, 1H), 5.54 (s, 2H), 3.91 (s, 3H), 3.26 (s,3H), 1.52 (s, 9H). N-tert-butyl-8-(3-cyanopyrazin-2-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 112

m/z: 580 [M + H]⁺ ¹H NMR (400 MHz, DMSO) δ 8.58 (d, J = 5.2 Hz, 1H),8.20 (d, J = 4.0 Hz, 2H), 7.87 (t, J = 1.9 Hz, 1H), 7.81 (d, J = 1.8 Hz,2H), 7.70 (s, 1H), 7.60 (dd, J = 5.0, 1.5 Hz, 1H), 7.57 (s, 1H), 6.89(s, 1H), 5.44 (s, 2H), 3.89 (s, 3H), 3.19 (s, 3H), 1.45 (s, 9H).N-tert-butyl-8-(4-carbamoylpyridin-2-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 113

m/z: 581 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 9.07 (d, J = 1.3 Hz, 1H),8.70 (d, J = 1.3 Hz, 1H), 8.01 (s, 1H), 7.53 (s, 3H), 6.70 (s, 1H), 5.55(s, 2H), 3.96 (s, 3H), 3.28 (s, 3H), 1.52 (s, 9H).N-tert-butyl-8-(6-carbamoylpyrimidin-4-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 114

m/z: 610 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 1.1 Hz, 1H),7.66 (s, 1H), 7.48 (d, J = 1.8 Hz, 2H), 7.44 (s, 1H), 6.91 (d, J = 1.1Hz, 1H), 6.73 (s, 1H), 5.48 (s, 2H), 3.92 (s, 3H), 3.70 (s, 3H), 3.25(s, 3H), 1.52 (s, 9H).N-tert-butyl-8-(4-carbamoyl-6-methoxypyridin-2-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 115

m/z: 594 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃) δ 8.60 (s, 1H), 8.32 (s, 1H),7.47 (d, J = 1.7 Hz, 2H), 7.39 (s, 1H), 6.70 (d, J = 13.0 Hz, 2H),5.51-5.44 (m, 2H), 3.76 (s, 3H), 3.26 (s, 3H), 2.23 (s, 3H), 1.52 (s,9H). N-tert-butyl-8-(5-carbamoyl-4-methylpyridin-3-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 116

m/z: 610 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 1.3 Hz, 1H),7.67 (d, J = 4.4 Hz, 1H), 7.53- 7.48 (m, 3H), 6.92 (s, 1H), 6.89 (d, J =1.3 Hz, 1H), 6.71 (s, 1H), 5.55 (d, J = 4.3 Hz, 1H), 5.48 (s, 2H), 3.97(s, 3H), 3.83 (d, J = 4.4 Hz, 3H), 3.26 (s, 3H), 1.52 (s, 9H).N-tert-butyl-8-(2-carbamoyl-6-methoxypyridin-4-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 117

m/z: 605 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃) δ 8.61 (s, 1H), 8.32 (s, 1H),7.47-7.42 (m, 3H), 6.71 (d, J = 16.4 Hz, 2H), 5.62- 5.48 (m, 2H), 3.77(s, 3H), 3.46 (s, 3H), 2.23 (s, 3H), 1.84 (s, 6H).8-(5-carbamoyl-4-methylpyridin-3-yl)-N-(2-cyanopropan-2-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 118

m/z: 573 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.26 (s, 1H),7.11 (dd, J = 6.8, 2.1 Hz, 2H), 6.96-6.86 (m, 1H), 6.71 (d, J = 15.7 Hz,2H), 5.88 (d, J = 16.5 Hz, 2H), 5.55 (d, J = 14.3 Hz, 2H), 3.77 (s, 3H),3.46 (s, 3H), 2.23 (s, 3H), 1.84 (s, 6H).8-(5-carbamoyl-4-methylpyridin-3-yl)-N-(2-cyanopropan-2-yl)-1-(3,5-difluorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 119

m/z: 591 [M + H]⁺ ¹H NMR (400 MHz, DMSO) δ 8.58 (d, J = 4.3 Hz, 1H),8.20 (s, 2H), 7.89 (d, J = 16.4 Hz, 3H), 7.71 (s, 1H), 7.58 (d, J = 19.5Hz, 2H), 6.91 (s, 1H), 5.51 (s, 2H), 3.89 (s, 3H), 1.74 (s, 6H).8-(4-carbamoylpyridin-2-yl)-N-(2-cyanopropan-2-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 120

Example 6.N-tert-butyl-N-(2-hydroxyethyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 121)

Step 1: N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-methylpropan-2-amine

To a solution of 2-(tert-butylamino)ethanol (500 mg, 4.27 mmol) in DMF(5 mL) was added imidazle (581 mg, 8.54 mmol) and TBSCl (962 mg, 63.41mmol) at 0° C. The mixture was stirred at RT overnight. Then the mixturewas extracted with EtOAc (100 mL), washed with water (20 mL×4) and driedover anhydrous Na₂SO₄. The organic phase was concentrated to affordN-(2-(tert-butyldimethylsilyloxy)ethyl)-2-methylpropan-2-amine (770 mg,78%) as a colorless oil. LCMS m/z [M+H]⁺ 232.2.

Step 2:7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid

To a solution of8-bromo-7-methoxy-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (100 mg, 0.25 mmol) in dioxane/H₂O (5/1, 2 mL) were added1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(104 mg, 0.50 mmol), PdCl₂(dppf) (36.6 mg, 0.05 mmol) and Cs₂CO₃ (161mg, 0.50 mmol) at RT under nitrogen. The reaction mixture was stirred at90° C. for 1 h under MW conditions. The reaction mixture was thenfiltered through celite and washed with DCM (50 mL). The filtrate wasconcentrated under vacuum; the crude product was purified by HPLC(mobile phase: acetonitrile/water (10 mM NH₄HCO₃) to afford the desiredcompound (100 mg, 90%) as an off-white solid. LCMS m/z=409 [M+H]⁺

Step 3:N-tert-butyl-N-(2-(tert-butyldimethylsilyloxy)ethyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution of7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (50 mg, 0.123 mmol) in DMF (1 mL) was addedN-(2-(tert-butyldimethylsilyloxy)ethyl)-2-methylpropan-2-amine (57 mg,0.246 mmol), DIEA (48 mg, 0.369 mmol) and HATU (70 mg, 0.185 mmol). Themixture was stirred at 80° C. for 4 h, then directly purified byCombi-Flash (mobile phase: acetonitrile/water (10 mM NH₄HCO₃)) to affordN-tert-butyl-N-(2-(tert-butyldimethylsilyloxy)ethyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(20 mg, 26%) as a white solid. LCMS m/z [M+H]⁺ 622.

Step 4:N-tert-butyl-N-(2-hydroxyethyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 121)

To a solution ofN-tert-butyl-N-(2-(tert-butyldimethylsilyloxy)ethyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(20 mg, 0.032 mmol) in THF (1 mL) was added TBAF (25 mg, 0.096 mmol).The mixture was stirred at RT for 4 h. Then the mixture was directlypurified by Combi-Flash (mobile phase: acetonitrile/water (10 mMNH₄HCO₃)) to affordN-tert-butyl-N-(2-hydroxyethyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(3 mg, 19%) as a white solid. LCMS m/z [M+H]⁺ 507.9. ¹H NMR (400 MHz,CDCl₃): 7.54-7.53 (m, 1H), 7.52 (s, 1H), 7.49-7.47 (m, 1H), 7.30 (d, J=2Hz, 1H), 7.25-7.23 (m, 1H), 6.65 (s, 1H), 6.51 (d, J=2 Hz, 1H), 5.47 (s,2H), 3.92-3.90 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.83-3.82 (m, 2H),1.57 (s, 9H).

The following compounds were prepared using procedures analogous tothose disclosed in Scheme 5.

Boronic Acid Amine Starting Starting Compound Material Material LC-MSNMR

m/z: 570 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.59 (s, 1H), 7.50 (s, 3H),7.31 (d, J = 2.2 Hz, 1H), 6.66 (s, 1H), 6.55 (d, J = 2.2 Hz, 1H), 5.44(s, 2H), 3.91 (t, J = 5.7 Hz, 2H), 3.89 (d, J = 3.8 Hz, 3H), 3.86 (s,3H), 3.86- 3.79 (m, 2H), 1.56 (s, 9H).N-tert-butyl-1-(3,5-dichlorophenyl)-N-(2-hydroxyethyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxamide Compound 122

m/z: 585 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J = 4.1 Hz, 1H),7.68 (ddd, J = 9.4, 7.4, 1.9 Hz, 1H), 7.46 (s, 3H), 7.19 (ddd, J = 7.0,4.9, 1.7 Hz, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 5.46 (s, 2H), 3.98- 3.85(m, 2H), 3.82 (d, J = 5.8 Hz, 5H), 1.56 (s, 9H).N-tert-butyl-1-(3,5-dichlorophenyl)-8-(2-fluoropyridin-3-yl)-N-(2-hydroxyethyl)-7-methoxy-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxamide Compound 123

m/z: 562 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): δ = 7.66 (s, 1 H), 7.22 (s, 1H), 6.63 (s, 2H), 6.58 (s, 1 H), 6.50 (s, 1 H), 6.43 (s, 1 H), 3.86-3.73 (m, 16 H), 1.51 (s, 9 H).N-tert-butyl-1-(3,5-dimethoxyphenyl)-N-(2-hydroxyethyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxamide Compound 124

m/z: 494 [M + H]⁺ 1-(8-isobutyl-7-methoxy-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carbonyl)- 2,2-dimethylpiperidin-4-oneCompound 125

m/z: 548 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): δ = 7.54-6.65 (m, 7 H), 6.64(s, 1H), 6.49 (d, J = 2.4 Hz, 1 H), 5.55 (s, 2 H), 4.32- 4.25 (m, 1 H),4.07- 4.00 (m, 1 H), 3.88- 3.87 (m, 6 H), 3.80 (s, 2 H), 2.17-1.65 (m, 7H), 1.15-0.98 (m, 6 H). (2-(hydroxymethyl)-2-isobutylpyrrolidin-1-yl)(7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-yl)methanone Compound 126

m/z: 562 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): δ = 7.53-7.52 (m, 1 H), 7.49(s, 1 H), 7.47-7.45(m, 1 H), 6.63 (s, 1 H), 6.50 (d, J = 2.4 Hz, 1 H),5.60- 5.52 (m, 2 H), 4.15- 4.08 (m 2 H), 4.02 (d, J = 9.2 Hz, 1 H), 3.87(s, 3 H), 3.86 (s, 3 H), 3.60 (d, J = 8.8 Hz, 1 H), 3.36 (s, 3 H), 2.05-(2-isobutyl-2-(methoxymethyl)pyrrolidin-1-yl)(7- 1.90 (m, 7 H), 1.05methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3- (m, 6 H).yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-yl)methanone Compound 127

m/z: 534 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.53 (dd, J = 3.2, 1.3 Hz,1H), 7.49 (s, 1H), 7.46 (dd, J = 5.1, 3.2 Hz, 1H), 7.29 (d, J = 2.2 Hz,1H), 7.27-7.25 (m, 2H), 6.64 (s, 1H), 6.51 (d, J = 2.2 Hz, 1H), 5.62-5.51 (m, 2H), 4.21- 4.12 (m, 1H), 4.05- 3.96 (m, 2H), 3.87 (t, J = 6.4Hz, 6H), 3.60 (d, J = 9.1 Hz, 1H),(2-ethyl-2-(methoxymethyl)pyrrolidin-1-yl)(7- 3.36 (s, 3H), 2.34-2.16methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen- (m, 1H), 2.10 (dt, J =3-yl)-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methanone 11.4, 5.3 Hz,1H), 1.94- Compound 128 1.71 (m, 4H), 0.88 (t, J = 7.5 Hz, 3H).

m/z: 582 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 7.55 (m, 2H), 7.48 (m, 1H),7.32 (d, 1H), 7.27 (m, 1H), 6.67 (s, 1H), 6.54 (d, 2H), 5.32 (s, 2H),4.20 (m, 1H), 4.10 (m, 1H), 3.90 (s, 6H), 3.38 (m, 1H), 2.90 (s, 3H),2.38 (m, 1H), 2.12 (m, 2H), 2.00 (m, 1H), 1.70 (s, 3H), 1.45 (s, 3H).(2,2-dimethyl-4-(methylsulfonyl)piperidin-1-yl)(7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methanone Compound 129

m/z: 536 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 7.55 (m, 2H), 7.48 (m, 1H),7.32 (d, 1H), 7.27 (m, 1H), 6.67 (s, 1H), 6.54 (d, 2H), 5.32 (s, 2H),4.28 (m, 1H), 4.00 (d, 1H), 3.88 (s, 6H), 3.45 (m, 2H), 1.90 (m, 2H),1.70 (s, 3H), 1.45 (s, 3H).((4R,5S)-4,5-dihydroxy-2,2-dimethylpiperidin-1-yl)(7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methanone Compound 130

m/z: 588 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 7.541-7.455 (m, 3H),7.298-7.254 (m, 2H) 6.638 (s, 1H), 6.510-6.505 (d, 1H), 5.544 (s, 2H),4.129- 4.087 (m, 2H), 3.871 (s, 3H), 3.860 (s, 3H), 3.827-3.821 (d, 2H),3.365 (s, 3H), 3.290- 3.213 (m, 1H), 2.890- 2.761 (m, 1H), 2.294- 2.173(m, 2H), 1.933- 1.879 (m, 2H).(7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(2-(methoxy-methyl)-2-(2,2,2-trifluoroethyl)pyrrolidin-1-yl)methanone Compound 131

m/z: 551 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 7.611 (s, 1H), 7.535-7.529(d, 2H, J = 2.4 Hz), 7.513- 7.507 (d, 1H, J = 2.4 Hz), 7.312-7.306 (d,1H, J = 2.4 Hz), 6.663 (s, 1H), 6.561-6.556 (d, 1H, J = 2.0 Hz), 5.526(s, 2H), 3.884 (s, 3H), 3.866 (s, 3H), 3.460 (s, 3H), 1.828 (s, 6H).N-(2-cyanopropan-2-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 132

m/z: 465 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 7.498-7.460 (m, 2H),7.223-7.207 (1H), 6.543 (s, 1H), 6.511 (s, 1H), 5.479 (s, 2H), 3.779 (s,3H), 3.450 (s, 3H), 2.218- 2.201 (d, 2H), 1.828 (s, 6H), 1.726-1.659 (m,1H), 0.792 (s, 3H), 0.775 (s, 3H).N-(2-cyanopropan-2-yl)-8-isobutyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxamide Compound 133

Example 7.1-(3,5-dimethoxyphenyl)-N-(4-hydroxy-2-methylbutan-2-yl)-7-methoxy-N-methyl-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 134)

Step 1: 3-methyl-3-(methylamino)butan-1-ol

A mixture of 3-(tert-butoxycarbonylamino)-3-methylbutanoic (434 mg, 2.0mmol) and LiAlH₄ (10 mL, 10 mmol, 1 mol/L in THF) in THF (10 mL) washeated at 60° C. under N₂ overnight. After cooling to room temperature,water (4 mL) was added, followed by 15% NaOH (1 mL aq). The mixture wasthen extracted with DCM:MeOH 10:1 (20 mL×3), washed with brine (10 mL),dried (Na₂SO₄), and evaporated to afford3-methyl-3-(methylamino)butan-1-ol (117 mg, yield 50%). m/z=118.2 [M+H]⁺

Step 2: 4-(tert-butyldiphenylsilyloxy)-N,2-dimethylbutan-2-amine

A mixture of 3-methyl-3-(methylamino)butan-1-ol (117 mg, 1.0 mmol),TBDPSCl (274 mg, 1.0 mmol) and imidazole (210 mg, 3.0 mmol) in DMF (10mL) was stirred at room temperature under N₂ for 4 hrs. Then the mixturewas diluted with EtOAc (80 mL) and washed with water (20 mL×3), brine(20 mL), dried (Na₂SO₄), and evaporated. The residue was purified byprep-TLC (silica gel:PE:EA=1:1) to afford4-(tert-butyldiphenylsilyloxy)-N,2-dimethylbutan-2-amine (80 mg, yield23%).

Step 3:8-bromo-N-(4-(tert-butyldiphenylsilyloxy)-2-methylbutan-2-yl)-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution of8-bromo-1-(3,5-dimethoxyphenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (69 mg, 0.15 mmol) in DMF (5 mL) was added4-(tert-butyldiphenylsilyloxy)-N,2-dimethylbutan-2-amine (54 mg, 0.15mmol), HATU (57 mg, 0.15 mmol) and diisopropyl ethylamine (59 mg, 0.45mmol) at RT under nitrogen. The reaction mixture was stirred at RT for 3h. then quenches with sodium bicarbonate (10 mL, 10%) and extracted withEtOAc (2×30 mL). The combined organic layers were washed with NaHCO₃solution (10 mL, 10% solution), brine (10 mL), and dried (Na₂SO₄). Thesolvent was removed under vacuum, and the crude product was purified bycolumn chromatography by using pet ether and ethyl acetate (3:1) aseluent to afford8-bromo-N-(4-(tert-butyldiphenylsilyloxy)-2-methylbutan-2-yl)-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(65 mg, 54%) as a light-yellow solid. m/Z=820.2 [M+Na]

Step 4:N-(4-(tert-butyldiphenylsilyloxy)-2-methylbutan-2-yl)-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution of8-bromo-N-(4-(tert-butyldiphenylsilyloxy)-2-methylbutan-2-yl)-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(27 mg, 0.034 mmol) in DMF (1.5 mL) was added1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21mg, 0.10 mmol), Pd(dppf)Cl₂ (4 mg, 0.0068 mmol) and NaHCO₃ (9 mg, 0.10mmol) at RT under nitrogen. The reaction mixture was degassed withnitrogen for 20 min and water (0.3 mL) was added at RT. The reactionmixture was stirred at 120° C. for 1 h under MW conditions. The reactionmixture was filtered through celite and washed with DCM (50 mL). Thefiltrate was concentrated under vacuum; the crude product was washedwith water (10 ml), brine (10 mL) and dried over sodium sulphate. Theorganic solvent was removed under vacuum; the crude product was purifiedby preparative HPLC(C18, A 10 mmol NH₄HCO₃, B. CH₃CN) to affordN-(4-(tert-butyldiphenylsilyloxy)-2-methylbutan-2-yl)-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(15 mg, 55%) as a white solid. m/Z=822.3 [M+Na]

Step 5:1-(3,5-dimethoxyphenyl)-N-(4-hydroxy-2-methylbutan-2-yl)-7-methoxy-N-methyl-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 134)

A mixture ofN-(4-(tert-butyldiphenylsilyloxy)-2-methylbutan-2-yl)-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(15 mg, 0.019 mmol) and TBAF (0.06 mL, 0.06 mmol, 1.0 mol·L⁻¹) in THF (2mL) was stirred at room temperature overnight. Then concentrated and theresidue was purified by Preparative HPLC(C18, A 10 mmol NH₄HCO₃, B.CH₃CN) to afford1-(3,5-dimethoxyphenyl)-N-(4-hydroxy-2-methylbutan-2-yl)-7-methoxy-N-methyl-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(6 mg, 57%) as a light-yellow solid. m/Z=562.3 [M+H]+; ¹H NMR (400 MHz,CDCl₃) δ ppm 7.69 (s, 1H), 7.30 (s, 1H), 6.73-6.72 (m, 2H), 6.64 (s,1H), 6.58 (s, 1H), 6.49 (d, J=2.4 Hz, 1H), 5.46 (s, 2H), 3.87 (s, 3H),3.85 (s, 3H), 3.81 (s, 6H), 3.77-3.73 (m, 2H), 3.28 (s, 3H), 2.20-2.17(m, 2H), 1.54 (s, 6H).

The following compounds were prepared using procedures analogous tothose disclosed in Scheme 6.

Boronic Acid Amine Starting Starting Compound Material Material LC-MSNMR

m/z: 577 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J = 4.1 Hz, 1H),7.61 (s, 1H), 7.15 (s, 1H), 6.83 (s, 1H), 6.68 (s, 1H), 6.64 (d, J = 2.2Hz, 2H), 6.53 (t, J = 2.2 Hz, 1H), 5.49 (s, 2H), 3.86-3.70 (m, 11H),3.28 (s, 3H), 2.20 (dd, J = 12.8, 6.3 Hz, 2H), 1.54 (s, 6H).1-(3,5-dimethoxyphenyl)-8-(2-fluoropyridin-3-yl)-N-(4-hydroxy-2-methylbutan-2-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Compound 135

Example 8.N-tert-butyl-1-(3,5-dichlorophenyl)-8-(1-(2-(dimethylamino)-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 136)

Step 1: tert-butyl4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)-3,5-dimethyl-1H-pyrazole-1-carboxylate

To a solution of8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(330 mg, 0.61 mmol) in dioxane/H₂O (5/1, 6 mL) was added tert-butyl3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(297 mg, 0.92 mmol), PdCl₂(dppf) (89 mg, 0.12 mmol) and Cs₂CO₃ (398 mg,1.22 mmol) at RT under nitrogen. The reaction mixture was stirred at 90°C. for 1 h under MW conditions. The reaction mixture was filteredthrough celite and washed with DCM (50 mL). The filtrate wasconcentrated in vacuum and the crude product was purified by columnchromatograph using pet ether: ethyl acetate as eluent to afford thedesired compound (230 mg, 56%) as an off-white solid.

Step 2:N-tert-butyl-1-(3,5-dichlorophenyl)-8-(3,5-dimethyl-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

A solution of tert-butyl4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)-3,5-dimethyl-1H-pyrazole-1-carboxylate(120 mg, 0.18 mmol) in DMF (5 mL) was stirred at 120° C. for 2 h underMW conditions. The solution was diluted with H₂O (50 mL), exacted withEA (20 mL×3). The combined organics were washed with brine (20 mL×2),dried with Na₂SO₄, and concentrated to give the crude product (100 mg,99%) as a pale yellow solid. m/z=654 [M+H]⁺.

Step 3: methyl2-(4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)-3,5-dimethyl-1H-pyrazol-1-yl)acetate(Compound 138)

To a solution ofN-tert-butyl-1-(3,5-dichlorophenyl)-8-(3,5-dimethyl-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(100 mg, 0.18 mmol) in DMF (3 mL) was added Cs₂CO₃ (117 mg, 0.36 mmol)and methyl 2-bromoacetate (55 mg, 0.36 mmol). The reaction mixture wasstirred at RT overnight, then directly purified by Combi-Flash (mobilephase: acetonitrile/water (10 mM NH₄HCO₃)) to afford methyl2-(4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)-3,5-dimethyl-1H-pyrazol-1-yl)acetate(100 mg, 88%) as a white solid. LCMS m/z=626 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.44-7.43 (m, 3H), 6.69 (s, 1H), 6.61 (s, 1H), 5.45 (s, 2H),4.79 (s, 2H), 3.78 (d, J=1.7 Hz, 6H), 3.24 (s, 3H), 2.00 (d, J=9.6 Hz,6H), 1.52 (s, 9H).

Step 4:8-(1-(2-amino-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 139)

A mixture of methyl2-(4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)-3,5-dimethyl-1H-pyrazol-1-yl)acetate(10 mg, 0.016 mmol) and NH₃ in MeOH (2 ml) was sealed up and heated to60° C. for 2 h. The solvents were removed to give the crude product,which was purified by preparative HPLC to give desired product (7 mg,70%) as a white solid. LCMS m/z=611 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.44-7.43 (m, 3H), 6.69 (s, 1H), 6.61 (s, 1H), 5.45 (s, 2H), 4.79 (s,2H), 3.78 (d, J=1.7 Hz, 6H), 3.24 (s, 3H), 2.00 (d, J=9.6 Hz, 6H), 1.52(s, 9H).

Step 5:2-(4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)-3,5-dimethyl-1H-pyrazol-1-yl)aceticacid (Compound 137)

To a solution of methyl2-(4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)-3,5-dimethyl-1H-pyrazol-1-yl)acetate(90 mg, 0.14 mmol) in the mixture of THF (3 mL) and H₂O (3 mL) was addedLiOH.H₂O (29 mg, 0.7 mmol) at RT. The reaction mixture was stirred at RTfor 16 h. The reaction mixture was and concentrated. The residue waspurified by Combi-Flash (mobile phase: acetonitrile/water (10 mMNH₄HCO₃)) to afford2-(4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)-3,5-dimethyl-1H-pyrazol-1-yl)aceticacid (80 mg, 91%) as a white solid. LCMS m/z=612 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.47-7.43 (m, 3H), 6.71 (s, 1H), 6.58 (s, 1H), 5.46 (s,2H), 4.93 (s, 2H), 3.78 (s, 3H), 3.24 (s, 3H), 2.06-2.01 (m, 6H), 1.52(s, 9H).

Step 6:N-tert-butyl-1-(3,5-dichlorophenyl)-8-(1-(2-(dimethylamino)-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 136)

To a solution of2-(4-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)-3,5-dimethyl-1H-pyrazol-1-yl)aceticacid (45 mg, 0.074 mmol) in DMF (1 mL) was added dimethylaminehydrochloride (12 mg, 0.147 mmol), HATU (42 mg, 0.11 mmol) and DIEA(38.2 mg, 0.296 mmol). The mixture was stirred at RT overnight. Then themixture was directly purified by Combi-Flash (mobile phase:acetonitrile/water (10 mM NH₄HCO₃)) to affordN-tert-butyl-1-(3,5-dichlorophenyl)-8-(1-(2-(dimethylamino)-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(20 mg, 43%) as a white solid. LCMS m/z=639 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.43 (s, 3H), 6.69 (s, 1H), 6.64 (s, 1H), 5.44 (s, 2H), 4.84(s, 2H), 3.77 (s, 3H), 3.24 (s, 3H), 3.08 (s, 3H), 2.98 (s, 3H), 2.00(s, 6H), 1.51 (s, 9H).

The following compounds were prepared using procedures analogous tothose disclosed in Scheme 7.

Amine Boronic Acid Starting Compound Starting Material Material LC-MSNMR

m/z: 625 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.44 (m, 3H), 6.70 (s,1H), 6.57 (s, 1H), 6.23- 6.21 (m, 1H), 5.46 (s, 2H), 4.66 (s, 2H), 3.79(s, 3H), 3.24 (s, 3H), 2.81 (d, J = 4.8 Hz, 3H), 2.01 (d, J = 15.0 Hz,6H), 1.52 (s, 9H).

m/z: 540 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.56-7.43 (m, 4H), 6.76 (s,1H), 6.69 (s, 1H), 5.45 (s, 2H), 3.82 (s, 3H), 3.25 (s, 3H), 2.11 (s,3H), 1.52 (s, 9H).

m/z: 597 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃) δ 7.48 (s, 4H), 6.79 (s, 1H),6.69 (s, 1H), 6.40 (s, 1H), 5.60 (s, 1H), 5.45 (s, 2H), 4.71 (s, 2H),3.83 (s, 3H), 3.25 (s, 3H), 2.05 (s, 3H), 1.50 (s, 9H).

m/z: 597 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.48 (m, 4H), 6.71 (d,J = 6.0 Hz, 2H), 6.10 (s, 1H), 5.60 (s, 1H), 5.45 (s, 2H), 4.74 (s, 2H),3.82 (s, 3H), 3.25 (s, 3H), 2.09 (s, 3H), 1.52 (s, 9H).

Example 9.N-tert-butyl-8-(4-carbamoyl-1-methyl-1H-pyrazol-3-yl)-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 144)

Step 1:8-(4-bromo-1-methyl-1H-pyrazol-3-yl)-N-tert-butyl-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 145)

To a solution ofN-tert-butyl-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(250 mg, 0.47 mmol) in DCM (10 mL) was added NBS (84 mg, 0.47 mmol). Themixture was stirred at RT for 6 h. Then the mixture was directlypurified by pre-TLC (peth:EA=3:2) to afford8-(4-bromo-1-methyl-1H-pyrazol-3-yl)-N-tert-butyl-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-1,4dihydrochromeno[4,3-c]pyrazole-3-carboxamide (200 mg, 70%) as a whitesolid. LCMS m/z=610[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.39 (s, 1H), 7.05(s, 1H), 6.69 (s, 1H), 6.67 (d, 2H), 6.51 (t, 1H), 5.51 (s, 2H), 3.88(s, 3H), 3.83 (s, 3H), 3.80 (s, 6H), 3.28 (s, 3H), 1.53 (s, 9H).

Step 2:N-tert-butyl-8-(4-cyano-1-methyl-1H-pyrazol-3-yl)-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 146)

To a solution of8-(4-bromo-1-methyl-1H-pyrazol-3-yl)-N-tert-butyl-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(90 mg, 0.15 mmol) in DMAc (3 mL) was added zinc cyanide (52 mg, 0.45mmol), zinc powder (30 mg, 0.45 mmol) and PdP[(t-Bu)3]2 (15 mg, 0.3mmol) at RT under nitrogen. The mixture was stirred at 120° C. for 1 hunder MW conditions. The mixture was filtered and directly purified bypurified by Combi-Flash (mobile phase: acetonitrile/water (10 mMNH₄HCO₃)) to affordN-tert-butyl-8-(4-cyano-1-methyl-1H-pyrazol-3-yl)-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(60 mg, 73%) as a white solid. LCMS m/z=557 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.77 (s, 1H), 7.29 (s, 1H), 6.69 (m, 3H), 6.55 (t, 1H), 5.54 (s,2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.82 (s, 6H), 3.29 (s, 3H), 1.54 (s,9H).

Step 3:N-tert-butyl-8-(4-carbamoyl-1-methyl-1H-pyrazol-3-yl)-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 144)

To a solution ofN-tert-butyl-8-(4-cyano-1-methyl-1H-pyrazol-3-yl)-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(20 mg, 0.36 mmol) in MeOH (1 mL) was added NH₃.H₂O (0.5 mL) and H₂O₂(0.5 mL, 30%) at RT. The mixture was stirred at RT overnight. Themixture was concentrated in vacuum and the residue was directly purifiedby Combi-Flash (mobile phase: acetonitrile/water (10 mM NH₄HCO₃)) toaffordN-tert-butyl-8-(4-carbamoyl-1-methyl-1H-pyrazol-3-yl)-1-(3,5-dimethoxyphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(6 mg, 29%) as a white solid. LCMS m/z=575 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.92 (s, 1H), 7.03 (s, 1H), 6.71 (s, 1H), 6.64 (d, 2H), 6.53 (t,1H), 5.53 (s, 2H), 3.89 (s, 3H), 3.82 (s, 6H), 3.80 (s, 3H), 3.29 (s,3H), 1.53 (s, 9H).

The following compounds were prepared using procedures analogous tothose disclosed in Scheme 8.

Amine Boronic acid Starting Compound Starting material material LC/MSNMR

m/z: 597 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.39 (s, 1H), 7.17-7.07 (m,2H), 6.97-6.87 (m, 2H), 6.70 (s, 1H), 5.54 (s, 2H), 3.87 (s, 3H), 3.82(s, 3H), 3.45 (s, 3H), 1.83 (s, 6H).

m/z: 618 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.44 (m, 2H), 7.42 (t,J = 1.8 Hz, 1H), 7.39 (s, 1H), 6.93 (s, 1H), 6.69 (s, 1H), 5.46 (s, 2H),3.88 (s, 3H), 3.82 (s, 3H), 3.24 (s, 3H), 1.51 (s, 9H).

m/z: 533 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, 1H), 7.22 (s, 1H),7.18-7.10 (m, 2H), 6.924-6.90 (m, 1H), 6.69 (s, 1H), 5.49 (s, 2H), 3.90(s, 3H), 3.88 (s, 3H), 3.26 (s, 3H), 1.52 (s, 9H).

m/z: 561 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.20 (s, 1H),7.16-7.09 (m, 2H), 6.95-6.90 (m, 1H), 6.69 (s, 1H), 5.49 (s, 2H),4.05-4.03 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87- 3.82 (m, 2H), 3.49(s, 2H), 1.53 (s, 6H).

m/z: 570 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.36 (s, 1H), 7.17-7.05 (m,2H), 6.96 (s, 1H), 6.95-6.85 (m, 1H), 6.70 (s, 1H), 5.47 (s, 2H),4.15-4.00 (m, 2H), 3.85-3.83 (m, 8H), 3.48 (s, 2H), 1.53 (s, 6H).

m/z: 533 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.37 (s, 1H), 7.15-7.10 (m,2H), 6.96-6.90 (m, 2H), 6.71 (s, 1H), 5.54 (s, 2H), 3.86 (s, 3H), 3.83(s, 3H), 3.45 (s, 3H), 1.84 (s, 6H).

m/z: 580 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): δ 8.669- 8.656 (d, 1H, J =5.2 Hz), 8.416 (s, 1H), 7.592-7.579 (d, 1H, J = 5.2 Hz), 7.499-7.494 (d,2H, J = 2.0 Hz), 7.453-7.444 (t, 1H, J = 1.6 Hz), 6.883 (s, 1H), 6.690(s, 1H), 5.632-5.484 (m, 4H), 3.765 (s, 3H), 3.260 (s, 3H), 1.510 (s,9H).

m/z: 564 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 8.91 (d, 1H), 8.67 (d, 1H),7.08 (t, 1H), 7.43 (s, 1H), 7.25 (m, 2H), 6.90 (s, 1H), 6.75 (s, 1H),5.50 (s, 2H), 3.84 (s, 3H), 3.28 (s, 3H), 1.53 (s, 9H).

m/z: 592 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J = 2.1 Hz, 1H),8.67 (d, J = 2.1 Hz, 1H), 8.08 (t, J = 2.1 Hz, 1H), 7.40 (s, 1H),7.26-7.22 (m, 2H), 6.87 (s, 1H), 6.74 (s, 1H), 5.49 (s, 2H), 4.11- 4.01(m, 2H), 3.89- 3.78 (m, 5H), 3.50 (s, 2H), 1.53 (s, 6H).

m/z: 576 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.91 (d, J = 2.0 Hz, 1H),8.66 (d, J = 2.0 Hz, 1H), 8.03 (J = 2.1 Hz, 1H), 7.16 (t, J = 1.7 Hz,1H), 7.03-7.00 (m, 2H), 6.87 (s, 1H), 6.70 (d, J = 5.7 Hz, 1H), 5.50 (s,2H), 3.84 (d, J = 4.1 Hz, 3H), 3.82 (s, 3H), 3.27 (s, 3H), 1.52 (s, 9H).

m/z: 604 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J = 2.1 Hz, 1H),8.67 (d, J = 2.1 Hz, 1H), 8.02 (t, J = 2.1 Hz, 1H), 7.14 (t, J = 1.7 Hz,1H), 7.04 (t, J = 2.0 Hz, 1H), 7.00 (t, J = 2.0 Hz, 1H), 6.86 (s, 1H),6.72 (s, 1H), 5.51 (s, 2H), 4.13- 4.04 (m, 2H), 3.87- 3.83 (m, 8H), 3.49(s, 2H), 1.53 (s, 6H).

m/z: 582 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃): 8.93 (d, 1H), 8.69 (d, 1H),8.04 (t, 1H), 7.17 (t, 1H), 7.04 (m, 2H), 6.89 (s, 1H), 6.72 (s, 1H),5.52 (s, 2H), 3.29 (s, 3H), 1.54 (s, 9H).

m/z: 600 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.91 (d, J = 2.1 Hz, 1H),8.68 (d, J = 2.1 Hz, 1H), 7.92 (t, J = 2.1 Hz, 1H), 6.84 (s, 1H), 6.72-6.64 (m, 3H), 6.60 (t, J = 2.3 Hz, 1H), 5.53 (s, 2H), 4.16-4.08 (m, 2H),3.89-3.78 (m, 11H), 3.49 (s, 2H), 1.54 (s, 6H).

m/z: 572 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.92 (d, J = 2.1 Hz, 1H),8.69 (d, J = 2.0 Hz, 1H), 7.92 (t, J = 2.0 Hz, 1H), 6.85 (s, 1H),6.72-6.67 (m, 3H), 6.59 (t, J = 2.2 Hz, 1H), 5.53 (s, 2H), 3.82-3.81 (m,9H), 3.28 (s, 3H), 1.52 (s, 9H).

m/z: 548 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J = 2.1 Hz, 1H),8.66 (d, J = 2.1 Hz, 1H), 8.07 (t, J = 2.1 Hz, 1H), 7.18-7.13 (m, 2H),7.02- 6.92 (m, 1H), 6.89 (s, 1H), 6.73 (s, 1H), 5.49 (s, 2H), 3.83 (s,3H), 3.27 (s, 3H), 1.52 (s, 9H).

m/z: 590 [M + H]⁺ ¹H NMR (400 MHz, DMSO) δ 8.89 (d, J = 2.0 Hz, 1H),8.50 (d, J = 2.0 Hz, 1H), 8.11-8.10 (m, 1H), 7.64-7.45 (m, 3H), 6.93 (s,1H), 6.83 (s, 1H), 5.41 (s, 2H), 4.73 (d, J = 4.5 Hz, 1H), 3.82 (s, 3H),1.55 (s, 3H), 1.42 (s, 3H).

m/z: 608 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J = 2.1 Hz, 1H),8.67 (d, J = 2.1 Hz, 1H), 8.07 (t, J = 2.1 Hz, 1H), 7.15 (dd, J = 6.8,2.1 Hz, 2H), 7.04-6.95 (m, 1H), 6.89 (s, 1H), 6.74 (s, 1H), 5.50 (s,2H), 4.53-4.47 (m, 1H), 4.39-4.32 (m, 1H), 3.84 (s, 3H), 3.61- 3.52 (m,1H), 3.10 (q, J = 13.8 Hz, 2H), 2.86-2.80 (m, 1H), 1.79 (s, 3H), 1.69(s, 3H).

m/z: 576 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J = 2.1 Hz, 1H),8.66 (d, J = 2.1 Hz, 1H), 8.07 (t, J = 2.1 Hz, 1H), 7.17-7.12 (m, 2H),7.02-6.92 (m, 1H), 6.88 (s, 1H), 6.74 (s, 1H), 5.50 (s, 2H), 4.13-4.03(m, 2H), 3.90-3.80 (m, 5H), 3.50 (s, 2H), 1.53 (s, 6H).

m/z: 581 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.73 (t, J = 1.8 Hz, 1H),7.56 (t, J = 1.5 Hz, 1H), 7.46 (t, J = 1.8 Hz, 1H), 7.22-7.11 (m, 2H),7.00-6.95 (m, 1H), 6.85 (s, 1H), 6.71 (s, 1H), 5.48 (s, 2H), 3.83 (s,3H), 3.27 (s, 3H), 1.52 (s, 9H).

m/z: 560 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J = 2.1 Hz, 1H),8.67 (d, J = 2.1 Hz, 1H), 8.01 (t, J = 2.1 Hz, 1H), 6.95-6.85 (m, 3H),6.78-6.74 (m, 1H), 6.71 (s, 1H), 5.51 (s, 2H), 3.84 (s, 3H), 3.83 (s,3H), 3.27 (s, 3H), 1.52 (s, 9H).

m/z: 518 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.86 (d, J = 2.0 Hz, 1H),8.66 (d, J = 2.0 Hz, 1H), 8.10 (t, J = 2.0 Hz, 1H), 7.56-7.47 (m, 2H),7.24-7.22 (m, 1H), 6.77 (s, 1H), 6.69 (s, 1H), 5.53 (s, 2H), 3.82 (s,3H), 3.28 (s, 3H), 1.52 (s, 9H).

m/z: 513 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃): 8.86 (d, 1H, J = 2.0 Hz),8.78 (d, 1H, J = 2.0 Hz), 8.64- 8.62 (m, 1H), 8.24 (t, 1H, J = 2.4 Hz),7.93- 7.89 (m, 1H), 7.77 (d, 1H, J = 8.4 Hz), 7.58 (s, 1H), 7.42-7.39(m, 1H), 6.70 (s, 1H), 6.26 (brs, 1H), 5.78 (brs, 1H), 5.47 (s, 2H),3.83 (s, 3H), 3.28 (s, 3H), 1.53 (s, 9H).

m/z: 608 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J = 2.1 Hz, 1H),8.67 (d, J = 2.1 Hz, 1H), 8.09 (t, J = 2.1 Hz, 1H), 7.50 (s, 3H), 6.86(s, 1H), 6.74 (s, 1H), 5.49 (s, 2H), 4.11- 4.03 (m, 2H), 3.90- 3.81 (m,5H), 3.50 (s, 2H), 1.53 (s, 6H).

m/z: 594 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J = 2.2 Hz, 1H),7.70 (d, J = 2.2 Hz, 1H), 7.54-7.44 (m, 3H), 6.86 (s, 1H), 6.73 (s, 1H),5.76 (s, 2H), 5.47 (s, 2H), 3.82 (s, 3H), 3.26 (s, 3H), 2.72 (s, 3H),1.52 (s, 9H).

m/z: 580 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.84 (d, J = 1.9 Hz, 1H),8.60 (d, J = 1.9 Hz, 1H), 8.03 (t, J = 1.9 Hz, 1H), 7.45-7.41 (m, 3H),6.81 (s, 1H), 6.66 (s, 1H), 5.41 (s, 2H), 3.76 (s, 3H), 3.19 (s, 3H),1.45 (s, 9H).

m/z: 579 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.79-7.69 (m, 2H), 7.56-7.40(m, 5H), 6.88 (s, 1H), 6.72 (s, 1H), 5.47 (s, 2H), 3.82 (s, 3H), 3.26(s, 3H), 1.52 (s, 9H).

m/z: 544 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.88 (d, J = 2.0 Hz, 1H),8.63 (d, J = 2.0 Hz, 1H), 8.03 (t, J = 2.1 Hz, 1H), 7.18 (s, 1H), 7.09-7.03 (m, 2H), 6.82 (s, 1H), 6.71 (s, 1H), 5.52 (s, 2H), 3.82 (s, 3H),3.28 (s, 3H), 2.44 (s, 3H), 1.52 (s, 9H).

Example 10.3-carbamoyl-5-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)pyridine1-oxide (Compound 174)

Step 1:3-carbamoyl-5-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)pyridine1-oxide

To a solution of5-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)nicotinamide(30 mg, 0.05 mmol) in CH₂Cl₂ (10 mL) was added m-CPBA (26 mg, 0.15 mmol)at 0° C. The mixture was stirred at RT overnight. The mixture wasconcentrated in vacuum and the residue was purified by Combi-Flash(mobile phase: acetonitrile/water (10 mM NH₄HCO₃)) to afford3-carbamoyl-5-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)pyridine1-oxide (20 mg, 65%) as a white solid. LCMS m/z=624 [M+H]⁺. ¹H NMR (400MHz, DMSO) δ 8.51 (t, J=1.4 Hz, 1H), 8.24 (t, J=1.5 Hz, 1H), 8.14 (s,1H), 7.80 (dd, J=3.0, 1.3 Hz, 4H), 7.56 (t, J=1.4 Hz, 1H), 6.92 (d,J=13.1 Hz, 2H), 5.43 (s, 2H), 3.96-3.88 (m, 2H), 3.84 (s, 3H), 3.73 (t,J=5.0 Hz, 2H), 3.43 (s, 2H), 1.42 (s, 6H).

The following compounds were prepared using procedures analogous tothose disclosed in Scheme 9.

Amine Boronic Acid Starting Compound Starting Material Material LC-MSNMR

m/z: 624 [M + H]⁺ ¹H NMR (400 MHz, DMSO) δ 8.51 (t, J = 1.4 Hz, 1H),8.24 (t, J = 1.5 Hz, 1H), 8.14 (s, 1H), 7.80 (dd, J = 3.0, 1.3 Hz, 4H),7.56 (t, J = 1.4 Hz, 1H), 6.92 (d, J = 13.1 Hz, 2H), 5.43 (s, 2H),3.96-3.88 (m, 2H), 3.84 (s, 3H), 3.73 (t, J = 5.0 Hz, 2H), 3.43 (s, 2H),1.42 (s, 6H).

m/z: 588 [M + H]⁺ ¹H NMR 400 MHz, CDCl₃) δ 8.56 (t, J = 1.6 Hz, 1H),8.43 (t, J = 1.6 Hz, 1H), 7.33- 7.32 (m, 1H), 6.84 (s, 1H), 6.70-6.69(dm, 3H), 6.62 (t, , J = 2.0 Hz, 1H), 5.54 (s, 2H), 3.84 (s, 9H), 3.29(s, 3H), 1.52 (s, 9H).

m/z: 592 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃) δ 8.77 (s, 1H), 8.40 (s, 1H),7.58 (s, 1H), 7.12 (d, J = 4.9 Hz, 2H), 7.03 (t, J = 8.5 Hz, 1H), 6.88(s, 1H), 6.72 (s, 1H), 5.51 (s, 2H), 4.07 (t, J = 3.6 Hz, 2H), 3.85 (m,5H), 3.50 (s, 2H), 1.53 (s, 6H).

m/z: 606 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃) δ 8.44 (s, 1H), 8.30 (s, 1H),7.57 (t, J = 1.6 Hz, 1H), 7.49 (d, J = 1.6 Hz, 2H), 7.36 (s, 1H), 6.86(s, 1H), 6.73 (s, 1H), 5.52 (s, 2H), 4.14-4.02 (m, 2H), 3.90-3.81 (m,5H), 3.50 (s, 2H), 1.53 (s, 6H).

Example 11.5-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)nicotinicacid (Compound 178)

Step15-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)nicotinicacid

To a solution of5-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)nicotinonitrile(50 mg, 0.085 mmol) in dioxane/H₂O (1/1, 2 mL) was added NaOH (17 mg,0.42 mmol). The mixture was stirred at 100° C. for 2 h under MWconditions. The mixture was directly purified by Combi-Flash (mobilephase: acetonitrile/water (10 mM NH₄HCO₃)) to afford5-(1-(3,5-dichlorophenyl)-3-(3,3-dimethylmorpholine-4-carbonyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)nicotinicacid (33 mg, 65%) as a white solid. LCMS m/z=609 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.75 (dd, J=11.8, 1.9 Hz, 2H), 7.97 (t, J=2.1 Hz, 1H),7.56-7.47 (m, 3H), 6.88 (s, 1H), 6.74 (s, 1H), 5.51 (s, 2H), 4.11-4.02(m, 2H), 3.86 (d, J=7.8 Hz, 5H), 3.50 (s, 2H), 1.53 (s, 6H).

The following compounds were prepared using procedures analogous tothose disclosed in Scheme 10.

Amine Boronic Acid Starting Compound Starting Material Material LC-MSNMR

m/z: 580 [M + H]⁺ ¹H NMR (400 MHz, MeOD) δ 8.01-7.87 (m, 2H), 7.67-7.66(m, 3H), 7.47 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 6.86 (s,2H), 5.39 (s, 1H), 6.83 (s, 2H), 5.39 (s, 1H), 3.85 (s, 3H), 3.24 (s,3H), 1.56 (s, 9H).

m/z: 598 [M + H]⁺ ¹H NMR (400 MHz, MeOD) δ 7.74 (dd, J = 7.0, 2.4 Hz,1H), 7.67 (t, J = 1.8 Hz, 1H), 7.63 (d, J = 1.9 Hz, 2H), 7.48- 7.44 (m,1H), 7.13- 7.08 (m, 1H), 6.80 (d, J = 7.5 Hz, 2H), 5.37 (s, 2H), 3.82(s, 3H), 3.24 (s, 3H), 1.55 (s, 9H).

Example 12.N-tert-butyl-8-(1-carbamoyl-1H-pyrazol-4-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 181)

Step 1:N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(1H-pyrazol-4-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution of8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(300 mg, 0.56 mmol) in dioxane/H₂O (10/1, 3 mL) were added4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (217 mg,1.12 mmol), Cs₂CO₃ (364 mg, 1.12 mmol), and Pd(dppf)Cl₂ (45 mg, 0.056mmol) at RT under nitrogen. The reaction mixture was stirred at 90° C.for 1 h under MW conditions. The reaction mixture was directly purifiedby Combi-Flash (mobile phase: acetonitrile/water (10 mM NH₄HCO₃)) toaffordN-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(1H-pyrazol-4-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(280 mg, 95%) as a white solid. LC-MS m/z=526 [M+H]⁺.

Step 2:N-tert-butyl-8-(1-carbamoyl-1H-pyrazol-4-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution ofN-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(1H-pyrazol-4-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(50 mg, 0.095 mmol) in CH₃CN (3 mL) were added NaOCN (10 mg, 0.19 mmol),HOAc (0.2 mL), and H₂O (0.2 mL). The reaction mixture was stirred at RTovernight. The mixture was diluted with NaHCO₃(aq.) (10 mL), extractedwith CH₂Cl₂ (10 mL*2). The combined organics were dried over Na₂SO₄, andconcentrated. The residue was purified by HPLC (mobile phase:acetonitrile/water (10 mM NH₄HCO₃) to affordN-tert-butyl-8-(1-carbamoyl-1H-pyrazol-4-yl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(20 mg, 38%) as a white solid. LCMS m/z=569 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.45 (d, J=0.5 Hz, 1H), 7.58-7.50 (m, 4H), 7.10 (s, 1H), 6.70(s, 1H), 5.46 (s, 2H), 3.92 (s, 3H), 3.26 (s, 3H), 1.52 (s, 9H).

Example 13.N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(5-ureidopyridin-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

Step 1:8-(5-acetamidopyridin-3-yl)-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 182)

To a solution of N8-(5-aminopyridin-3-yl)-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(5 mg, 0.01 mmol), in AcOH (1 mL) were added NaOCN (2 mg, 0.03 mmol).The reaction mixture was stirred at RT for 1 h. The mixture was pouredinto NaHCO₃ (aq.) (5 mL), extracted with CH₂Cl₂ (5 mL*2). The combinedorganics were dried over Na₂SO₄, and concentrated. The solution waspurified by HPLC (mobile phase: acetonitrile/water (10 mM NH₄HCO₃) toafford8-(5-acetamidopyridin-3-yl)-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(2 mg, 33%) as a as a white solid. LCMS m/z=594 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.59 (d, J=2.3 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H), 7.99 (s, 1H),7.52 (d, J=1.8 Hz, 2H), 7.46 (t, J=1.8 Hz, 1H), 7.37 (s, 1H), 6.90 (s,1H), 6.71 (s, 1H), 5.47 (s, 2H), 3.83 (s, 3H), 3.26 (s, 3H), 2.22 (s,3H), 1.52 (s, 9H).

Step 2:N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(5-ureidopyridin-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 183)

A solution of8-(5-aminopyridin-3-yl)-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(20 mg, 0.036 mmol) in NaOCN (7 mg, 0.11 mmol), HOAc (0.05 mL), andTHF/H₂O (1/1, 0.1 Ml) was stirred at RT overnight. The mixture waspoured into NaHCO₃(aq.) (10 mL), extracted with CH₂Cl₂ (10 mL*2). Thecombined organics were dried over Na₂SO₄, and concentrated. The solutionwas purified by HPLC (mobile phase: acetonitrile/water (10 mM NH₄HCO₃)to affordN-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-(5-ureidopyridin-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(5 mg, 24%) as a as a white solid. LCMS m/z=595 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.36 (s, 1H), 8.11 (s, 1H), 7.88 (d, J=16.0 Hz, 2H), 7.47 (d,J=1.6 Hz, 2H), 7.40 (d, J=1.6 Hz, 1H), 6.84 (s, 1H), 6.65 (s, 1H), 5.42(s, 2H), 5.13 (s, 2H), 3.75 (s, 3H), 3.24 (s, 3H), 1.52 (s, 9H).

Example 14.4-(7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carbonyl)-3,3-dimethylpiperazine-1-carbonitrile(Compound 184)

Step 1:7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid

To a solution of8-bromo-7-methoxy-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (1 g, 2.46 mmol) in dioxane/H₂O (5/1, 10 mL) was added methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate(1.02 g, 4.93 mmol), PdCl₂(dppf) (360 mg, 0.49 mmol) and Cs₂CO₃ (1.6 g,4.93 mmol) at RT under nitrogen. The reaction mixture was stirred at100° C. for 1 h under MW conditions. The reaction mixture was filteredthrough celite and washed with DCM (50 mL). The filtrate wasconcentrated under vacuum; the crude product was purified by HPLC(mobile phase: acetonitrile/water (10 mM NH₄HCO₃) to afford the desiredcompound (300 mg, 30%) as an off-white solid. LCMS m/z=409 [M+H]⁺.

Step 2: tert-butyl4-(7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carbonyl)-3,3-dimethylpiperazine-1-carboxylate

A mixture of7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (50 mg, 0.123 mmol), HATU (51 mg, 0.135 mmol), tert-butyl3,3-dimethylpiperazine-1-carboxylate (34 mg, 0.135 mmol) and DIPEA (48mg, 0.369 mmol) in DMF (3 ml) was was stirred at RT overnight. Then themixture was purified by Combi-Flash (mobile phase: acetonitrile/water(10 mM NH₄HCO₃) to afford tert-butyl4-(7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carbonyl)-3,3-dimethylpiperazine-1-carboxylate(55 mg, 37.2%) as a white solid. LCMS m/z=605 [M+H]⁺.

Step 3:(2,2-dimethylpiperazin-1-yl)(7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methanonehydrochloride

A mixture of tert-butyl4-(7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carbonyl)-3,3-dimethylpiperazine-1-carboxylate(55 mg, 0.091 mmol) and Dioxane/HCl (4M, 1 ml) in DCm (2 ml) was stirredat RT overnight. Then the mixture was concentrated to get(2,2-dimethylpiperazin-1-yl)(7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methanonehydrochloride (40 mg, 54%) as a white solid. LCMS m/z=505 [M+H]⁺.

Step 4:4-(7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carbonyl)-3,3-dimethylpiperazine-1-carbonitrile

A mixture of(2,2-dimethylpiperazin-1-yl)(7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)methanonehydrochloride (20 mg, 0.037 mmol), cyanic bromide (8 mg, 0.074 mmol) andTEA (12 mg, 0.111 mol) was stirred at RT overnight. Then the mixture waspurified by column chromatography (silica gel: 200-300 mesh,PE:EtOAc=1:1) to get4-(7-methoxy-8-(1-methyl-H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carbonyl)-3,3-dimethylpiperazine-1-carbonitrile(10 mg, 50%) as a white solid. LCMS m/z=530.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.53-7.52 (m, 1H), 7.49-7.47 (m, 2H), 7.30-7.29 (m, 1H),7.24-7.23 (m, 1H), 6.51 (d, J=2.4 Hz, 1H), 5.48 (s, 2H), 4.29-4.27 (m,2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.56 (m, 2H), 3.25 (s, 2H), 1.65 (s,6H).

Example 15.N-tert-butyl-7-methoxy-N-methyl-8-(5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 185)

Step 1:N-tert-butyl-8-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

A mixture of8-bromo-N-tert-butyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(47.5 mg, 0.1 mmol), tert-butyldimethyl(prop-2-ynyloxy)silane (51 mg,0.3 mmol), CuI (6 mg, 0.03 mmol), Pd(PPh₃)₄ (14 mg, 0.012 mmol), TEA(0.15 ml) in DMF (2 ml) was stirred at 105° C. for 10 h. The crudeproduct was purified by preparative HPLC to give the desired pureproduct (15 mg, 33%) as a yellow liquid. ¹H NMR (400 MHz, CDCl₃):7.48-7.51 (m, 2H), 7.21-7.22 (m, 1H), 6.91 (s, 1H), 6.56 (s, 1H), 5.50(s, 2H), 4.53 (s, 2H), 3.85 (s, 3H), 3.28 (s, 3H), 1.53 (s, 9H), 0.94(s, 9H), 0.15 (s, 6H). m/z=566.2 [M+H]⁺.

Step 2:N-tert-butyl-8-(3-hydroxyprop-1-ynyl)-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution ofN-tert-butyl-8-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(56.5 mg, 0.1 mmol) in THF (5 mL) was added TBAF (1 ml, 0.2 mmol) at RT.The reaction mixture was stirred at RT for 2 h. The reaction mixture wasevaporated and diluted with EtOAc (50 ml) and washed with brine. Themixture was filtered and concentrated to afford the desired crudecompoundN-tert-butyl-8-(3-hydroxyprop-1-ynyl)-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(30 mg, 66%) as an off-white solid, which was used to the next stepwithout further purification. m/z=452.1 [M+H⁺.

Step 3: Methyl3-(3-(tert-butyl(methyl)carbamoyl)-7-methoxy-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)propiolate

A mixture ofN-tert-butyl-8-(3-hydroxyprop-1-ynyl)-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(50 mg, 0.11 mmol), NaCN (6 mg, 0.11 mmol), MnO₂ (145 mg, 1.65 mmol) inTHF (5 ml) and MeOH (5 ml) was refluxed for 5 h. The crude product waspurified by preparative HPLC to give the desired pure product (5 mg,12%) as a white solid. ¹H NMR (400 MHz, CDCl₃): 7.51-7.54 (m, 2H),7.20-7.22 (m, 1H), 7.00 (s, 1H), 6.58 (s, 1H), 5.56 (s, 2H), 3.89 (s,3H), 3.82 (s, 3H), 3.29 (s, 3H), 1.53 (s, 9H). m/z=480.0 [M+H]⁺. and 6(5 mg, 13%) as a white solid. ¹H NMR (400 MHz, CDCl₃): 7.51-7.54 (m,2H), 7.19 (s, 1H), 6.98 (s, 1H), 6.57 (s, 1H), 3.88 (s, 3H), 3.28 (s,3H), 1.52 (s, 9H). m/z=466.0 [M+H]⁺.

Step 4:8-(3-amino-3-oxoprop-1-ynyl)-N-tert-butyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 186)

A solution of methyl3-(3-(tert-butyl(methyl)carbamoyl)-7-methoxy-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)propiolate(10 mg, 0.021 mmol) and NH₃ in MeOH (3 ml) was heated to 60° C. for 2 hin a sealed tube. The solvent was removed to give crude product, whichwas purified by preparative HPLC to give desired product (5 mg, 50%) asa white solid. ¹H NMR (400 MHz, CDCl₃): 7.50-7.54 (m, 2H), 7.20-7.22 (m,1H), 6.98 (s, 1H), 6.59 (s, 1H), 5.55 (s, 2H), 3.88 (s, 3H), 3.28 (s,3H), 1.53 (s, 9H). m/z=465.2 [M+H]⁺.

Step 5:N-tert-butyl-7-methoxy-N-methyl-8-(5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 185)

A solution of methyl3-(3-(tert-butyl(methyl)carbamoyl)-7-methoxy-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)propiolate(6 mg, 0.0125 mmol) in NH₂NH₂H₂O (2 ml) was heated to 100° C. for 2 hunder MW conditions. The solvent was removed to give crude product,which was purified by preparative HPLC to giveN-tert-butyl-7-methoxy-N-methyl-8-(5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(2 mg, 25%) as a white solid. ¹H NMR (400 MHz, CDCl₃): 7.57-7.59 (m,2H), 7.25-7.26 (m, 1H), 7.04 (s, 1H), 6.69 (s, 1H), 5.56 (s, 2H), 5.37(s, 1H), 3.98 (s, 3H), 3.30 (s, 3H), 1.54 (s, 9H). m/z=480.0 [M+H]⁺.

The following compound was prepared using procedures analogous to thosedisclosed in Scheme 14.

Hydrazinyl Amine Starting Starting Compound material Material LC-MS NMR

CH₃NH₂NH₂ m/z: 494 [M + H]⁺ ¹H NMR (500 MHz, CDCl₃) δ 7.57-7.44 (m, 2H),7.23-7.17 (m, 1H), 6.72 (s, 1H), 6.67 (s, 1H), 5.54 (s, 2H), 5.43 (s,1H), 3.83 (s, 3H), 3.45 (s, 3H), 3.29 (s, 3H), 1.53 (s, 9H).

Example 16.1-(3,5-dichlorophenyl)-N-ethyl-N-(ethylsulfonyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 188)

Step 1:1-(3,5-dichlorophenyl)-N-ethyl-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

A mixture of1-(3,5-dichlorophenyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (100 mg, 0.212 mmol), HATU (97 mg, 0.255 mmol), ethanaminehydrochloride (21 mg, 0.255 mmol) in DMF (3 ml) was stirred at RTovernight. Then the mixture was purified by Combi-Flash (mobile phase:acetonitrile/water (10 mM NH₄HCO₃) to afford1-(3,5-dichlorophenyl)-N-ethyl-7-methoxy-8-(1-methyl-H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(100 mg, 94%) as a white solid. LCMS m/z [M+H]⁺ 498.1. ¹H NMR (400 MHz,CDCl₃): 7.598 (s, 1H), 7.551-7.546 (d, 2H, J=2.0 Hz), 7.509-7.504 (d,1H, J=2.0 Hz), 7.310-7.304 (d, 1H, J=2.4 Hz), 6.863-6.850 (m, 1H), 6.652(s, 1H), 6.555-6.550 (d, 1H, J=2.0 Hz), 5.617 (s, 2H), 3.880 (s, 3H),3.863 (s, 3H), 3.510-3.441 (m, 2H), 1.273-1.237 (t, 3H, J=2.0 Hz).

Step 2:1-(3,5-dichlorophenyl)-N-ethyl-N-(ethylsulfonyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 188)

At 0° C., to a solution of1-(3,5-dichlorophenyl)-N-ethyl-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(100 mg, 0.2 mmol) in DMF, was added NaH (24 mg, 0.6 mmol) andethanesulfonyl chloride (77 mg, 0.6 mmol). The mixture was stirred at70° C. under N₂ overnight, quenched by sat NH₄Cl and purified bypreparative HPLC to get1-(3,5-dichlorophenyl)-N-ethyl-N-(ethylsulfonyl)-7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(15 mg, 12.7%) as a white solid. LCMS m/z [M+H]⁺ 590.1. ¹H NMR (400 MHz,CDCl₃): 7.63 (s, 1H), 7.53 (m, 3H), 7.33-7.31 (m, 1H), 6.65 (s, 1H),6.56 (d, 1H, J=2.0 Hz), 5.53 (s, 2H), 4.41-4.35 (m, 2H), 3.89 (s, 3H),3.87 (s, 3H), 3.74-3.69 (m, 2H), 1.45-1.41 (m, 6H).

Example 17.N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-8-(2-methoxy-5-methylpyridin-3-yl)-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 189)

Step 1:1-(3,5-dichlorophenyl)-8-(2-fluoro-5-methylpyridin-3-yl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid

To a solution of8-bromo-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (160 mg, 0.34 mmol) in dioxane/H₂O (5/1, 5 mL) was added2-fluoro-5-methylpyridin-3-ylboronic acid (106 mg, 0.68 mmol),PdCl₂(dppf) (50 mg, 0.068 mmol) and KF (39 mg, 0.68 mmol) at RT undernitrogen. The reaction mixture was stirred at 90° C. for 2 h under MWconditions. The reaction mixture was filtered through celite and washedwith DCM (50 mL). The filtrate was concentrated in vacuum and the crudeproduct was purified by purified by preparative HPLC to afford thedesired compound (80 mg, 47%) as an off-white solid. LCMS m/z [M+H]⁺500.

Step 2:N-tert-butyl-1-(3,5-dichlorophenyl)-8-(2-fluoro-5-methylpyridin-3-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution of1-(3,5-dichlorophenyl)-8-(2-fluoro-5-methylpyridin-3-yl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (40 mg, 0.08 mol) in DMF (3 mL) was addedN,2-dimethylpropan-2-amine (14 mg, 0.16 mmol), HATU (45 mg, 0.12 mmol)and diisopropyl ethyl amine (21 mg, 0.16 mmol) at RT under nitrogen. Thereaction mixture was stirred at RT for 3 h, then the mixture waspurified by Combi-Flash (mobile phase: acetonitrile/water (10 mMNH₄HCO₃) to afford the desired compound (10 mg, 22%) as a white solid.LCMS (ESI) m/z=569 [M+H]⁺.

Step 3:N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-8-(2-methoxy-5-methylpyridin-3-yl)-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 189)

To a solution ofN-tert-butyl-1-(3,5-dichlorophenyl)-8-(2-fluoro-5-methylpyridin-3-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(5 mg, 0.009 mol) in CH₃OH (1 mL) was added sodium methanolate (1.5 mg,0.027 mmol) at RT. The reaction mixture was stirred at 90° C. for 2 hunder MW conditions. The mixture was purified by Combi-Flash (mobilephase: acetonitrile/water (10 mM NH₄HCO₃) to afford the desired compound(2 mg, 39%) as a white solid. LCMS (ESI) m/z=581 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.93 (d, J=1.6 Hz, 1H), 7.49 (d, J=1.8 Hz, 2H), 7.41 (t,J=1.8 Hz, 1H), 7.24 (d, J=2.3 Hz, 1H), 6.77 (s, 1H), 6.68 (s, 1H), 5.45(s, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.25 (s, 3H), 2.26 (s, 3H), 1.52(s, 9H).

Example 18.N-tert-butyl-1-(3,5-dichlorophenyl)-8-(1-(2,3-dihydroxypropyl)-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compounds 190, 191 and 192)

Step 1:1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg,2.57 mmol) and 4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (501 mg, 2.57mmol) in DMF (10 mL) was added Cs₂CO₃, DMF, OC (1.25 g, 3.85 mmol). Thereaction mixture was stirred at RT overnight. The solution was filteredand concentrated to give the desired compound (500 mg, 63%) as a yellowoil. LCMS (ESI) m/z=309 [M+H]⁺.

Step 2:N-tert-butyl-1-(3,5-dichlorophenyl)-8-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution of8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(50 mg, 0.093 mmol) in dioxane/H₂O (5/1, 2 mL) were added1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(57 mg, 0.19 mmol), PdCl₂(dppf) (8 mg, 0.009 mmol) and Cs₂CO₃ (62 mg,0.19 mmol) at RT under nitrogen. The reaction mixture was stirred at 90°C. for 2 h under MW conditions. The mixture was purified by preparativeHPLC (mobile phase: acetonitrile/water, 10 mM) to affordN-tert-butyl-1-(3,5-dichlorophenyl)-8-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(30 mg, 51%) as a white solid. LCMS (ESI) m/z=640 [M+H]⁺.

Step 3:N-tert-butyl-1-(3,5-dichlorophenyl)-8-(1-(2,3-dihydroxypropyl)-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution ofN-tert-butyl-1-(3,5-dichlorophenyl)-8-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(30 mg, 0.05 mmol) in THF (3 mL) was added 1M HCl (aq., 0.6 mL) at 0° C.The solution was stirred at rt overnight Then the solution was dilutedwith CH₂Cl₂ (100 mL), washed with sat.NaHCO₃, dried over Na₂SO₄, andconcentrated. The crude was purified by preparative HPLC (mobile phase:acetonitrile/water (10 mM) to affordN-tert-butyl-1-(3,5-dichlorophenyl)-8-(1-(2,3-dihydroxypropyl)-1H-pyrazol-4-yl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(20 mg, 67%) as a white solid. LCMS (ESI) m/z=600[M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.71 (s, 1H), 7.55-7.53 (m, 3H), 7.51 (s, 1H), 7.07 (s,1H), 6.68 (s, 1H), 5.44 (s, 2H), 4.27 (d, J=5.1 Hz, 2H), 4.11-4.08 (m,1H), 3.90 (s, 3H), 3.68-3.59 (m, 2H), 3.26 (s, 3H), 1.52 (s, 9H). Chiralseparation of Compound 190 gave Compound 191 and its stereoisomerCompound 192. Stereochemistry of both Compound 191 and Compound 192 aretentatively assigned.

The following compounds were prepared using procedures analogous tothose disclosed in Scheme 17.

Amine Boronic Acid Starting Compound Starting Material Material LC-MSNMR

m/z: 600 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.71 (s, 1H), 7.55-7.53 (m,3H), 7.51 (s, 1H), 7.07 (s, 1H), 6.68 (s, 1H), 5.44 (s, 2H), 4.27 (d, J= 5.1 Hz, 2H), 4.11-4.08 (m, 1H), 3.90 (s, 3H), 3.68- 3.59 (m, 2H), 3.26(s, 3H), 1.52 (s, 9H).

m/z: 600 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.71 (s, 1H), 7.55-7.53 (m,3H), 7.51 (s, 1H), 7.07 (s, 1H), 6.68 (s, 1H), 5.44 (s, 2H), 4.27 (d, J= 5.1 Hz, 2H), 4.11-4.08 (m, 1H), 3.90 (s, 3H), 3.68- 3.59 (m, 2H), 3.26(s, 3H), 1.52 (s, 9H). Stereochemistry is tentatively assigned.

m/z: 600 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.71 (s, 1H), 7.54 (d, J =1.9 Hz, 3H), 7.51 (s, 1H), 7.07 (s, 1H), 6.68 (s, 1H), 5.44 (s, 2H),4.27 (d, J = 5.1 Hz, 2H), 4.10 (s, 1H), 3.90 (s, 3H), 3.64 (dd, J = 8.9,4.5 Hz, 2H), 3.26 (s, 3H), 1.52 (s, 9H). Stereochemistry is tentativelyassigned.

Example 19.N-tert-butyl-8-(1-hydroxypropan-2-yloxy)-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 193)

Step 1:N-tert-butyl-8-hydroxy-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

At −10° C., BCl₃ was added toN-tert-butyl-8-isopropoxy-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(200 mg, 0.44 mmol) and stirred at −10° C. for 2 h. Then the resultingmixture was added to the sat.NaHCO₃ (20 ml) at 0° C., extracted with DCM(50 ml*3), dried and evaporated to getN-tert-butyl-8-hydroxy-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(220 mg, crude) as a white solid. LCMS m/z [M+H]⁺ 414.

Step 2:N-tert-butyl-8-(1-hydroxypropan-2-yloxy)-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 193)

A mixture ofN-tert-butyl-8-hydroxy-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(15 mg, 0.036 mmol), 2-bromopropan-1-ol (7.4 mg, 0.054 mmol) and Cs₂CO₃(35 mg, 0.108 mmol) in DMF (1 ml) was stirred at RT for 5 h. Then themixture was purified by preparative HPLC to getN-tert-butyl-8-(1-hydroxypropan-2-yloxy)-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(10 mg, 59%) as a white solid. LCMS m/z [M+H]⁺ 472.0. ¹H NMR (400 MHz,CDCl₃): 7.52-7.47 (m, 2H), 7.23-7.21 (m, 1H), 6.60 (s, 1H), 6.44 (s,1H), 5.46-5.38 (m, 2H), 3.90-3.86 (m, 1H), 3.83 (s, 3H). 3.6 (t, 1H,J=6.0 Hz), 3.25 (s, 3H), 2.76 (t, 1H, J=6.4 Hz), 1.51 (s, 9H), 1.11 (d,3H, J=6.4 Hz).

Example 20.N-tert-butyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-8-(1H-1,2,3-triazol-4-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 194)

Step 1:N-tert-butyl-8-ethynyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

A mixture of8-bromo-N-tert-butyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(500 mg, 1.05 mmol), tributyl(ethynyl)stannane (1.65 g, 5.25 mmol),Pd(PPh₃)₂Cl₂ (147 mg, 0.21 mmol), PPh₃ (110 mg, 0.42 mmol), and TEA (318mg, 3.15 mmol) in DME (10 ml) and toluene (5 ml) was heated at 140° C.by microwave for 5 h. Then the mixture was purified by columnchromatography (silica gel: 200-300 mesh, PE:EtOAc=10:1) to getN-tert-butyl-8-ethynyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(390 mg, 88%) as a white solid. LCMS m/z [M+H]⁺ 422.1.

Step 2:N-tert-butyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-8-(1H-1,2,3-triazol-4-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 194)

A mixture ofN-tert-butyl-8-ethynyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(110 mg, 0.261 mmol), NaN₃ (85 mg, 1.306 mmol), sodium ascorbate (103mg, 0.522 mmol) and CuSO₄ (42 mg, 0.261 mmol) in t-BuOH (3 ml), toluene(3 ml) and water (3 ml) was stirred at 80° C. under N₂ for 5 h. Then themixture was filtered with celite and extracted with DCM (50 ml*3) andMeOH (5 ml*3) to afford the crude product. The residue was purified byPrep-TLC (silica gel: DCM:EA=10:1) to getN-tert-butyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-8-(1H-1,2,3-triazol-4-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(25 mg, 18%) as a white solid. LCMS m/z [M+H]+ 465.0. ¹H NMR (400 MHz,CDCl₃): 7.65 (s, 1H), 7.56-7.55 (m, 2H), 7.25-7.23 (m, 2H), 6.69 (s,1H), 5.55 (s, 2H), 3.976 (s, 3H), 3.281 (s, 3H), 1.515 (s, 9H).

Example 21.N-tert-butyl-1-(3,5-dichlorophenyl)-8-(2-fluoro-3-(hydroxymethyl)phenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 195)

Step 1:N-tert-butyl-1-(3,5-dichlorophenyl)-8-(2-fluoro-3-formylphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

To a solution of8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(50 mg, 0.093 mmol) in dioxane/H₂O (5/1, 2 mL) were added2-fluoro-3-formylphenylboronic acid (35 mg, 0.186 mmol), KF (11 mg,0.186 mmol), and Pd(dppf)Cl₂ (14 mg, 0.019 mmol) at RT under nitrogen.The reaction mixture was stirred at 90° C. for 2 h under MW conditions.The reaction mixture was directly purified by Combi-Flash (mobile phase:acetonitrile/water (10 mM NH₄HCO₃) to affordN-tert-butyl-1-(3,5-dichlorophenyl)-8-(2-fluoro-3-formylphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(20 mg, 37%) as a white solid. LCMS m/z [M+H]⁺ 582.

Step 2:N-tert-butyl-1-(3,5-dichlorophenyl)-8-(2-fluoro-3-(hydroxymethyl)phenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 195)

To a solution ofN-tert-butyl-1-(3,5-dichlorophenyl)-8-(2-fluoro-3-formylphenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(20 mg, 0.034 mmol) in CH₃OH (2 mL) and THF (0.5 mL) was added NaBH₄(2.6 mg, 0.069 mmol). The mixture was filtered, concentrated andpurified by preparative HPLC (10 mM NH₄HCO₃) to giveN-tert-butyl-1-(3,5-dichlorophenyl)-8-(2-fluoro-3-(hydroxymethyl)phenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(15 mg, 75%) as a white solid. LCMS m/z [M+H]⁺ 584. ¹H NMR (400 MHz,CDCl₃) δ 7.37 (d, J=1.8 Hz, 2H), 7.31-7.22 (m, 2H), 7.09-6.97 (m, 2H),6.73 (s, 1H), 6.59 (s, 1H), 5.34 (s, 2H), 4.65 (s, 2H), 3.67 (s, 3H),3.13 (s, 3H), 1.40 (s, 9H).

Example 22.N-(tert-butyl)-8-((1SR,2SR)-2-carbamoylcyclopropyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

Step 1:N-(tert-butyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-vinyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide

A mixture of8-bromo-N-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(100 mg, 0.186 mmol), potassium trifluoro(vinyl)borate (5 mg, 0.372mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.1 eq.) and TEA (2 eq.) in 2 mL of EtOH (0.1mol/L) was allowed to reflux for 3 hours under N₂. The reaction mixturewas concentrated and purified by preparative TLC (DCM) to affordN-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-vinyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(85 mg, yield: 94.44%) as a white solid. LCMS: m/Z=487 (M+H)⁺.

Step 2: (1RS,2SR)-ethyl2-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)cyclopropanecarboxylate(Compound 197) and (1SR,2SR)-ethyl2-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)cyclopropanecarboxylate(Compound 198)

A mixture of compoundN-tert-butyl-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-8-vinyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(85 mg, 0.175 mmol), ethyl diazoacetate (200 mg, 10 eq.) in 5 mL oftoluene was sealed up and heated at 110° C. for 3 days. The reactionmixture was concentrated and purified by preparative HPLC to affordisomer 1 (10 mg, 10%) as a white solid and isomer 2 (25 mg, 25%) as awhite solid.

Compound 197: LCMS: m/Z=572[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.53-7.51(m, 2H). 7.50-7.49 (m, 1H), 6.82 (s, 1H), 6.51 (s, 1H), 5.44-5.33 (m,2H), 3.91-3.88 (m, 2H), 3.78 (s, 3H), 3.23 (s, 3H), 2.25-2.23 (m, 1H),2.0-1.99 (m, 1H), 1.48 (s, 9H), 1.28-1.26 (m, 1H), 1.17-1.15 (m, 1H),1.03-1.01 (m, 3H). Stereochemistry is tentatively assigned.

Compound 198: LCMS: m/Z=572 [M+H]+. ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.50(m, 1H), 7.45-7.44 (m, 2H), 6.56 (s, 1H), 6.43 (s, 1H), 5.39-5.38 (m,2H), 4.16-4.14 (m, 2H), 3.83 (s, 3H), 3.24-3.23 (m, 4H), 2.54-2.50 (m,1H), 1.51 (s, 9H), 1.44-1.39 (m, 1H), 1.29-1.26 (m, 3H), 0.92-0.89 (m,1H). Stereochemistry is tentatively assigned.

Step 3:(1SR,2SR)-2-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)cyclopropanecarboxylicacid (Compound 204)

To a solution of (1SR,2SR)-ethyl2-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)cyclopropanecarboxylate(Compound 198) (20 mg, 0.035 mmol) in MeOH/H₂O (3:1) (4 mL) was addedLiOH.H₂O (10 eq.). The reaction mixture was stirred at room temperatureovernight. The solvent was concentrated and purified by Prep-TLC(DCM/MeOH=20:1) to afford2-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)cyclopropanecarboxylicacid (17 mg, yield: 89.5%) as a white solid. LCMS: m/z=544 [M+H]⁺. ¹HNMR (400 mHz, CDCl₃) δ 7.51-7.50 (m, 2H). 7.45-7.44 (m, 1H), 6.57 (s,1H), 6.45 (s, 1H), 5.40-5.38 (m, 2H), 3.83 (s, 3H), 3.24 (s, 3H),2.56-2.53 (m, 1H), 1.47 (s, 9H), 1.46-1.43 (m, 2H), 1.15-1.10 (m, 1H).

Step 4:N-(tert-butyl)-8-((1SR,2SR)-2-carbamoylcyclopropyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 201)

A mixture of compound2-(3-(tert-butyl(methyl)carbamoyl)-1-(3,5-dichlorophenyl)-7-methoxy-1,4-dihydrochromeno[4,3-c]pyrazol-8-yl)cyclopropanecarboxylicacid (from Compound 204) (10 mg, 0.0184 mmol), NH₄Cl (5 eq.), HATU (1.2eq, 8.5 mg), DIPEA (3 eq.) in 3 mL of DMF was stirred at roomtemperature overnight. The reaction mixture was concentrated andpurified by preparative HPLC to affordN-tert-butyl-8-(2-carbamoylcyclopropyl)-1-(3,5-dichlorophenyl)-7-methoxy-N-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(8 mg, yield: 80.16%) as a white solid. LC MS: m/z=543 [M+H]+; ¹H NMR(400 MHz, CDCl₃) δ 7.51-7.50 (m, 1H). 7.47-7.46 (m, 2H), 6.57 (s, 1H),6.43 (s, 1H), 5.44 (bs, 1H), 5.35-5.31 (m, 3H), 3.23 (s, 3H), 3.02 (s,3H), 2.54-2.50 (m, 1H), 1.46 (s, 9H), 1.45-1.40 (m, 1H), 1.34-1.30 (m,1H), 0.89-0.84 (m, 1H).

The following compounds were prepared using procedures analogous tothose disclosed in Scheme 21.

Amine Starting Compound Material LC-MS NMR

m/z: 543 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.50 (m, 1H), 7.47-7.46(m, 2H), 6.57 (s, 1H), 6.43 (s, 1H), 5.44 (bs, 1H), 5.35-5.31 (m, 3H),3.23 (s, 3H), 3.02 (s, 3H), 2.54- 2.50 (m, 1H), 1.46 (s, 9H), 1.45-1.40(m, 1H), 1.34-1.30 (m, 1H), 0.89-0.84 (m, 1H).

m/z: 544 [M + H]⁺ ¹H NMR (400 MHz, CDCl3) δ 7.51-7.50 (m, 2H), 7.45-7.44(m, 1H), 6.57 (s, 1H), 6.45 (s, 1H), 5.40-5.38 (m, 2H), 3.83 (s, 3H),3.24 (s, 3H), 2.56-2.53 (m, 1H), 1.47 (s, 9H), 1.46-1.43 (m, 2H),1.15-1.10 (m, 1H).

m/z: 512 [M + H]⁺ 1H NMR (400 MHz, Chloroform-d) δ 7.08 (dd, J = 7.0,2.3 Hz, 2H), 6.98 (td, J = 8.9, 4.5 Hz, 1H), 6.54 (s, 1H), 6.44 (s, 1H),5.39 (s, 2H), 3.80 (s, 3H), 3.24 (s, 3H), 2.67 (brs, 1H), 2.50-2.54 (m,1H), 1.49-1.53 (m, 11H), 0.85-0.92 (m, 1H).

m/z: 526 [M + H]⁺ 1H NMR (400 MHz, Chloroform-d) δ 7.10 (dd, J = 7.3,2.3 Hz, 2H), 6.98 (tt, J = 8.7, 2.3 Hz, 1H), 6.56 (s, 1H), 6.44 (s, 1H),5.39 (s, 2H), 3.82 (s, 3H), 3.70 (s, 3H), 3.25 (s, 3H), 2.51 (ddd, J =9.2, 6.7, 4.3 Hz, 1H), 1.48 (s, 9H), 1.40 (dt, J = 9.3, 4.8 Hz, 1H),0.83-0.87 (m, 2H).

m/z: 511 [M + H]⁺ 1H NMR (400 MHz, Chloroform-d) δ 7.12 (dd, J = 7.3,2.3 Hz, 2H), 6.99 (tt, J = 8.7, 2.3 Hz, 1H), 6.57 (s, 1H), 6.48 (s, 1H),5.55 (s, 1H), 5.47-5.29 (m, 2H), 3.83 (s, 3H), 3.24 (s, 3H), 2.51 (ddd,J = 9.2, 6.7, 4.3 Hz, 1H), 1.51 (s, 9H), 1.43 (dt, J = 9.3, 4.8 Hz, 1H),1.36-1.25 (m, 1H), 0.85 (ddd, J = 8.1, 6.7, 4.4 Hz, 1H).

Example 23.N-tert-butyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-8-(1H-1,2,4-triazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 207)

Step 1:N³-tert-butyl-7-methoxy-N³-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3,8-dicarboxamide

A mixture ofN-tert-butyl-8-cyano-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(200 mg, 0.47 mmol), 30% H₂O₂ (2 mL) and NH₄OH (2 mL) in MeOH (10 mL)was heated at 50° C. overnight. After cooling to room temperature, thereaction was diluted with EtOAc (60 mL) and washed with water (10 mL×3),brine (20 mL), dried (Na₂SO₄), and evaporated to affordN₃-tert-butyl-7-methoxy-N3-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3,8-dicarboxamide(151 mg, 72%) as a white solid which used directly without furtherpurification. m/z=441.1 [M+H]⁺.

Step 2:(E)-N3-tert-butyl-N8-((dimethylamino)methylene)-7-methoxy-N3-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3,8-dicarboxamide

A mixture ofN₃-tert-butyl-7-methoxy-N3-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3,8-dicarboxamide(30 mg, 0.068 mmol) and DMF-DMA (24 mg, 0.20 mmol) in 1,4-dioxane (3 mL)was heated at 80° C. for 2 hrs under N₂. After cooling to roomtemperature, then the reaction was concentrated to afford(E)-N³-tert-butyl-N⁸-((dimethylamino)methylene)-7-methoxy-N³-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3,8-dicarboxamide(35 mg, 100%) as a light-yellow oil which used directly without furtherpurification. m/z=496 [M+H]⁺.

Step 3:N-tert-butyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-8-(1H-1,2,4-triazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(Compound 207)

To a solution of(E)-N³-tert-butyl-N⁸-((dimethylamino)methylene)-7-methoxy-N3-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3,8-dicarboxamide(10 mg, 0.02 mmol) in AcOH (1 mL) at 0° C., 80% N₂H₄.H₂O (3 mg, 0.06mmol) was added. Then the mixture was stirred at room temperature for 2hrs. Then the reaction was diluted with EtOAc (60 mL) and washed withwater (10 mL×3), NaHCO₃(sat.) (10 mL×3), brine (20 mL), dried (Na₂SO₄),evaporated. The residue was purified by Pre-TLC (silica gel: PE:EA=1:1)to affordN-tert-butyl-7-methoxy-N-methyl-1-(thiophen-3-yl)-8-(1H-1,2,4-triazol-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(5 mg, 48%) as a white solid. m/z=465.0 [M+H]. ¹H NMR (400 MHz, CDCl₃) δppm 11.46 (br, 1H), 7.88-7.85 (m, 2H), 7.55-7.54 (m, 2H), 7.26 (m, 1H),6.72 (s, 1H), 5.56 (s, 2H), 4.03 (s, 3H), 3.29 (s, 3H), 2.86 (s, 3H),1.51 (s, 9H).

The following compound was prepared using procedures analogous to thosedisclosed in Scheme 21.

Hydrazinyl Amine Starting Starting Compound material material LC/MS NMR

MeN₂H₄

m/z: 479 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ ppm 7.87 (s, 1H), 7.49 (s,1H), 7.44 (d, J = 5.2 Hz, 1H), 7.20 (d, J = 5.2 Hz, 1H), 6.92 (s, 1H),6.68 (s, 1H), 5.55 (s, 2H), 3.82 (s, 3H), 3.68 (s, 3H), 3.27 (s, 3H),1.51 (s, 9H).

Example 24. EC₅₀ of cyclic AMP production in CHO FSHR cells+EC₂₀ FSH(Assay A)

2500 Cho-FSHR-LUC-1-1-43 cells were plated per well in 5 al of phenolred free DMEM/F12+1% FBS. Cells were plated in 384 well, solid white lowvolume plates (Greiner 784075) by Multidrop. Cells were assayed byadding 100 al of 2×EC₂₀ FSH/IBMX in DMEM/F12+0.1% BSA) by Multidrop to 2al of test compound stamped in 384 well plates (compounds are diluted1:50). The final FSH concentration was 0.265 pM, and the final IBMXconcentration was 200 μM. The compound plate map was as follows: Column1: 2 μl of DMSO; Column 2: 2 μl of DMSO; Columns 3-12 and 13-24: 2 μl oftest compound, diluted 1:4 in 100% DMSO, or 2 μl of FSH, diluted 1:4 inDMEM/F12+0.1% BSA. The starting concentration for FSH was 50 nM (finalconcentration was 0.5 nM). Furthermore, Column 23 contained 2 μl ofEC₁₀₀ FSH reference (100×) (diluted in DMEM/F12+0.1% BSA) at a finalconcentration of 0.5 nM, and Column 24 contained 2 μl of 1 mM AS707664/2reference compound 2. 5 μl of compound+EC₂₀ FSH mixture were transferredto cell plates (1:2 dilution into 5 μl of cell media) The plates wereincubated at 37° C. for 1 h. 10 μl of mixed HTRF (CisBio #62AM4PEC)reagents were added per well and incubated at room temperature for 1 h.The plates were read on Envision using the cAMP HTRF—low volume 384 wellprotocol. The readout was the calculated fluorescence ratio (665 nm/620nm). Values given in percent (%) indicate the percental effect(response) at a certain concentration of agonist relative to the maximumresponse of the FSH standard. The results are provided below.

Example 25. Rat granulosa EC₅₀ FSH (Assay B)

The assay was performed pursuant to the teaching of Yanofsky et al.(2006) Allosteric activation of the follicle-stimulating hormone (FSH)receptor by selective, nonpeptide agonists (JBC 281(19): 13226-13233,which is incorporated by reference in the disclosure of the invention).The results are provided below.

The data is interpreted according to the following:

Compound number Assay A (nM) Assay B (nM) 1 ++++ +++ 2 ++++ +++ 3 +++++++ 4 +++ + 5 +++ ++ 6 ++++ ++ 7 +++ ++ 8 ++++ ++ 9 ++++ ++ 10 ++++ +++11 ++++ 12 ++++ +++ 13 +++ 14 ++++ +++ 15 ++++ 16 ++++ ++ 17 ++++ ++ 18+++ ++ 19 ++++ ++ 20 ++++ ++ 21 ++++ +++ 22 ++++ +++ 23 ++++ +++ 24 +++++++ 25 ++++ +++ 26 +++ ++ 27 +++ + 28 ++++ ++ 29 +++ ++ 30 ++ ++ 31 +++++ 32 +++ ++ 33 ++++ +++ 34 ++++ +++ 35 ++++ 36 ++++ +++ 37 +++ + 38 +++++ 39 +++ ++ 40 ++++ +++ 41 +++ ++ 42 ++++ +++ 43 ++++ +++ 44 ++++ +++45 ++++ 46 +++ ++ 47 +++ 48 +++ ++ 49 ++++ +++ 50 ++++ ++ 51 +++ ++ 52+++ ++ 53 +++ ++ 54 ++++ +++ 55 ++++ +++ 56 +++ ++ 57 +++ ++ 58 +++ + 59+++ + 60 ++++ ++ 61 ++++ +++ 62 ++++ +++ 63 +++ ++ 64 +++ ++ 65 ++++ +++66 ++++ +++ 67 ++++ ++ 68 ++++ ++ 69 ++++ +++ 70 ++++ +++ 71 +++ ++ 72++++ +++ 73 ++++ ++ 74 ++++ +++ 75 +++ +++ 76 +++ + 77 ++++ +++ 78 +++++++ 79 +++ ++ 80 ++++ ++ 81 +++ ++ 82 ++++ + 83 ++++ ++ 84 +++ ++ 85+++ + 86 ++++ ++ 87 +++ ++ 88 +++ ++ 89 ++++ ++ 90 ++++ ++ 91 ++++ +++92 ++++ +++ 93 ++++ +++ 94 ++++ ++++ 95 +++ +++ 96 ++++ ++++ 97 ++++++++ 98 ++++ ++ 99 ++++ +++ 100 ++++ +++ 101 ++++ +++ 102 ++++ +++ 103+++ + 104 +++ + 105 ++++ +++ 106 +++ + 107 ++++ ++ 108 ++++ +++ 109 +++++++ 110 ++++ +++ 111 +++ ++ 112 +++ ++ 113 ++++ +++ 114 +++ ++ 115 ++++++ 116 ++++ +++ 117 ++++ +++ 118 ++++ +++ 119 ++++ ++ 120 ++++ +++ 121+++ + 122 +++ ++ 123 ++++ +++ 124 +++ 125 ++++ +++ 126 +++ 127 +++ ++128 +++ 129 +++ 130 +++ ++ 131 +++ +++ 132 +++ ++ 133 ++++ 134 +++ + 135++++ +++ 136 ++++ +++ 137 ++++ ++ 138 ++++ ++ 139 ++++ +++ 140 ++++ ++141 ++++ +++ 142 ++++ +++ 143 +++ 144 + 145 ++++ ++ 146 ++++ ++ 147++++ + 148 ++++ +++ 149 ++++ +++ 150 ++++ +++ 151 ++++ +++ 152 153 +++++++ 154 ++++ ++++ 155 ++++ ++++ 156 ++++ +++ 157 ++++ ++++ 158 ++++ +++159 ++++ +++ 160 ++++ +++ 161 ++++ +++ 162 ++++ ++ 163 ++++ ++ 164 ++++++++ 165 ++++ +++ 166 ++++ ++ 167 ++++ +++ 168 ++++ ++ 169 ++++ ++ 170++++ ++ 171 ++++ ++++ 172 ++++ +++ 173 ++++ +++ 174 ++++ +++ 175 +++++++ 176 ++++ +++ 177 ++++ +++ 178 ++++ ++++ 179 +++ ++ 180 +++ 181 +++++++ 182 ++++ ++++ 183 ++++ +++ 184 ++++ +++ 185 +++ ++ 186 +++ 187 ++++++ 188 ++++ ++ 189 +++ ++ 190 +++ + 191 +++ ++ 192 ++ 193 +++ ++ 194++++ + 195 +++ +++ 196 ++++ ++ 197 +++ + 199 ++++ ++ 205 +++ 206 ++++ ++207 ++++ ++ 208 +++ + + >500 nM; ++ 101-500 nM; +++ 10-100 nM; ++++ <10nM.

Example 26. Pharmaceutical Preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 3 lof bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid,sterile filtered, transferred into injection vials, is lyophilized understerile conditions and is sealed under sterile conditions. Eachinjection vial contains 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention is melted with 100 g of soy lecithin and 1400 g ofcocoa butter, is poured into moulds and is allowed to cool. Eachsuppository contains 20 mg of active ingredient.

(C) Solution: A solution is prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g ofNa₂HPO₄.12H₂O and 0.1 g of benzalkonium chloride in 940 ml ofbidistilled water. The pH is adjusted to 6.8, and the solution is madeup to 1 1 and sterilized by irradiation. This solution could be used inthe form of eye drops.

(D) Ointment: 500 mg of an active ingredient according to the inventionis mixed with 99.5 g of Vaseline under aseptic conditions.

(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate is pressed to give tablets in aconventional manner in such a way that each tablet contains 10 mg ofactive ingredient.

(F) Coated tablets: Tablets are pressed analogously to Example E andsubsequently are coated in a conventional manner with a coating ofsucrose, potato starch, talc, tragacanth and dye.

(G) Capsules: 2 kg of an active ingredient according to the inventionare introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contains 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 60 l of bidistilled water is sterile filtered,transferred into ampoules, is lyophilized under sterile conditions andis sealed under sterile conditions. Each ampoule contains 10 mg ofactive ingredient.

(I) Inhalation spray: 14 g of an active ingredient according to theinvention are dissolved in 10 l of isotonic NaCl solution, and thesolution is transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 ml) corresponds to a dose of about 0.14mg.

While a number of embodiments of this invention are described herein, itis apparent that the basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1. A method for treating a FSHR-mediated disorder in a subjectin need thereof, comprising the step of administering to said subject acompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is O; Y is O;Z is N; each R is independently hydrogen, C₁₋₆ aliphatic, aryl, a 3-8membered saturated or partially unsaturated carbocyclic ring, a 3-7membered heterocyclic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each of which is optionally substituted; ortwo R groups on the same atom are taken together with the atom to whichthey are attached to form an aryl ring, a 3-8 membered saturated orpartially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted; Ring A is phenyl; R¹ is —OR; R²is aryl, a 3-8 membered saturated or partially unsaturated carbocyclicring, or a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,each of which is optionally substituted; R³ is an optionally substitutedphenyl; each R⁴ is independently —R, halogen, -haloalkyl, —OR, —SR, —CN,—NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂,—NRSO₂R, or —N(R)₂; R⁵ is an optionally substituted C₁₋₆ aliphatic; andR⁶ is an optionally substituted C₁₋₆ aliphatic; or R⁵, R⁶, and Ztogether form an optionally substituted 3-8 membered heterocylic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur; n is 0; and p is
 1. 2. The method of claim 1, wherein R² is a6-membered aryl ring, a 3-membered carbocyclic ring, or a 5-6 memberedmonocyclic heteroaryl ring having 1-4 nitrogen atoms, each of which isoptionally substituted.
 3. The method of claim 2, wherein R² is


4. The method of claim 1, wherein R³ is


5. The method of claim 1, wherein R⁵ is methyl, t-butyl,


6. The method of claim 1, wherein R⁶ is methyl, ethyl, or t-butyl. 7.The method of claim 1, wherein the compound of Formula I is a compoundof formula I-e:

or a pharmaceutically acceptable salt thereof.
 8. The method of claim 1,wherein the compound is selected from

or a pharmaceutically acceptable salt thereof.
 9. The method of claim 1,wherein the compound is

or a pharmaceutically acceptable salt thereof.
 10. The method of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 11. The method of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 12. The method of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 13. The method of claim1, wherein the compound modulates FSHR activity.
 14. The method of claim1, wherein the administration of the compound stimulates folliculardevelopment in the subject.
 15. The method of claim 1, wherein theFSHR-mediated disorder is selected from hypogonadotropic hypogonadism,isolated idiopathic hypogonadotropic hypogonadism, Kallmann syndrome,idiopathic hypogonadotropic hypogonadism, craniopharyngioma, combinedpituitary hormone deficiency, fertile eunuch syndrome, mass lesion,pituitary adenoma, cyst, metastatic cancer to the sella, infiltrativelesion, hemochromatosis, sarcoidosis, histiocytosis, lymphoma,lymphocytic hypophysitis, meningitis, pituitary apoplexy,hyperprolactinemia, hypothyroidism, intentional secondary hypogonadism,pituitary infarction, sheehan syndrome, anorexia nervosa, congenitaladrenal hyperplasia, or a disorder related to GnRH deficiency.